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Papers - Oba, Junna

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Medical AI and AI for Medical Sciences.

Sakurada K, Ishikawa T, Oba J, Kuno M, Okano Y, Sakamaki T, Tamura T

JMA journal 8 ( 1 ) 26 - 37 2025.01

Research paper (scientific journal), Joint Work, ISSN 2433-328X

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Using a Systems Engineering Approach to Build a PCR Testing System at a Medical School During the COVID-19 Pandemic

J Oba, M Toriya, Y Uwamino, K Matsuo

Risk Management and Healthcare Policy, 649-662 17 649 - 662 2024

Research paper (scientific journal), Joint Work, Lead author, Accepted, ISSN 1179-1594

Background: During the COVID-19 pandemic, there was an increasing need to expand diagnostic testing in hospitals. At Keio University Hospital (KUH), clinical staff were concerned that the demand for PCR testing might exceed the capacity of the Clinical Laboratory. In response, basic researchers at Keio University School of Medicine (KUSM) set out to build a new, collaborative, PCR testing system. To be authorized to perform such diagnostic PCR testing, KUSM registered its core laboratory as an external clinical laboratory (ECL). Methods: In the pandemic, there was a pressure to build the PCR system quickly. Speed required discussions that developed a shared understanding of the unprecedented, new KUH/KUSM PCR system. To design, construct, and archive the new PCR testing system, we used a systems engineering (SE) approach. This included diagram visualization of functional flows and application of the Unified Architecture Framework (UAF), both of which are often used in system building. We considered daily demand for PCR testing at KUH and KUSM, and daily COVID-19 infections in Japan. Results: We operated the collaborative PCR testing system from August 2020 to June 2022. Given public health insurance reimbursement policies, KUH focused on individuals with suspicious symptoms, while the ECL at KUSM screened samples from asymptomatic individuals. KUSM performed about half as many tests as KUH. Interviewing KUH staff revealed that diagrams helped promote a better understanding of the KUH/KUSM PCR testing system. Conclusion: When designing temporary systems that may be repurposed in the future, we suggest using an SE approach with diagrams and UAF perspectives. This approach will enable stakeholders to understand what is being proposed to be built, and facilitate achieving an informed consensus on the proposed system. We suggest that SE approaches should be widely used in projects that involve building and operating complex, collaborative systems, and documenting the process.

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Multi-modal molecular programs regulate melanoma cell state

Andrews M.C., Oba J., Wu C.J., Zhu H., Karpinets T., Creasy C.A., Forget M.A., Yu X., Song X., Mao X., Robertson A.G., Romano G., Li P., Burton E.M., Lu Y., Sloane R.S., Wani K.M., Rai K., Lazar A.J., Haydu L.E., Bustos M.A., Shen J., Chen Y., Morgan M.B., Wargo J.A., Kwong L.N., Haymaker C.L., Grimm E.A., Hwu P., Hoon D.S.B., Zhang J., Gershenwald J.E., Davies M.A., Futreal P.A., Bernatchez C., Woodman S.E.

Nature Communications (Nature Communications) 13 ( 1 ) 4000 2022.07

Research paper (scientific journal), Joint Work, Lead author, Accepted

Melanoma cells display distinct intrinsic phenotypic states. Here, we seek to characterize the molecular regulation of these states using multi-omic analyses of whole exome, transcriptome, microRNA, long non-coding RNA and DNA methylation data together with reverse-phase protein array data on a panel of 68 highly annotated early passage melanoma cell lines. We demonstrate that clearly defined cancer cell intrinsic transcriptomic programs are maintained in melanoma cells ex vivo and remain highly conserved within melanoma tumors, are associated with distinct immune features within tumors, and differentially correlate with checkpoint inhibitor and adoptive T cell therapy efficacy. Through integrative analyses we demonstrate highly complex multi-omic regulation of melanoma cell intrinsic programs that provide key insights into the molecular maintenance of phenotypic states. These findings have implications for cancer biology and the identification of new therapeutic strategies. Further, these deeply characterized cell lines will serve as an invaluable resource for future research in the field.

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SARS-CoV-2 RT-qPCR testing of pooled saliva samples: A case study of 824 asymptomatic individuals and a questionnaire survey in Japan

Oba J., Taniguchi H., Sato M., Takanashi M., Yokemura M., Sato Y., Nishihara H.

PLoS ONE (PLoS ONE) 17 ( 5 May ) e0263700 2022.05

Research paper (scientific journal), Joint Work, Lead author, Accepted

From the beginning of the COVID-19 pandemic, the demand for diagnostic and screening tests has exceeded supply. Although the proportion of vaccinated people has increased in wealthier countries, breakthrough infections have occurred amid the emergence of new variants. Pooled-sample COVID-19 testing using saliva has been proposed as an efficient, inexpensive, and non-invasive method to allow larger-scale testing, especially in a screening setting. In this study, we aimed to evaluate pooled RT-qPCR saliva testing and to compare the results with individual tests. Employees of Philips Japan, Ltd. were recruited to participate in COVID-19 screening from October to December 2020. Asymptomatic individuals (n = 824) submitted self-collected saliva samples. Samples were tested for the presence of SARS-CoV-2 by RT-qPCR in both 10-sample pools and individual tests. We also surveyed participants regarding their thoughts and behaviors after the PCR screening project. Two of the 824 individuals were positive by RT-qPCR. In the pooled testing, one of these two had no measurable Ct value, but showed an amplification trend at the end of the PCR cycle. Both positive individuals developed cold-like symptoms, but neither required hospitalization. Of the 824 participants, 471 responded to our online questionnaire. Overall, while respondents agreed that PCR screening should be performed regularly, the majority were willing to undergo PCR testing only when it was provided for free or at low cost. In conclusion, pooled testing of saliva samples can support frequent large-scale screening that is rapid, efficient, and inexpensive.

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Reprogramming of bivalent chromatin states in NRAS mutant melanoma suggests PRC2 inhibition as a therapeutic strategy

CJ Terranova, M Tang, M Maitituoheti, AT Raman, AK Ghosh, J Schulz, ...

Cell reports 36 (3) (Cell Reports) 36 ( 3 ) 109410 2021.07

Research paper (scientific journal), Joint Work, Accepted, ISSN 2211-1247

The dynamic evolution of chromatin state patterns during metastasis, their relationship with bona fide genetic drivers, and their therapeutic vulnerabilities are not completely understood. Combinatorial chromatin state profiling of 46 melanoma samples reveals an association of NRAS mutants with bivalent histone H3 lysine 27 trimethylation (H3K27me3) and Polycomb repressive complex 2. Reprogramming of bivalent domains during metastasis occurs on master transcription factors of a mesenchymal phenotype, including ZEB1, TWIST1, and CDH1. Resolution of bivalency using pharmacological inhibition of EZH2 decreases invasive capacity of melanoma cells and markedly reduces tumor burden in vivo, specifically in NRAS mutants. Coincident with bivalent reprogramming, the increased expression of pro-metastatic and melanocyte-specific cell-identity genes is associated with exceptionally wide H3K4me3 domains, suggesting a role for this epigenetic element. Overall, we demonstrate that reprogramming of bivalent and broad domains represents key epigenetic alterations in metastatic melanoma and that EZH2 plus MEK inhibition may provide a promising therapeutic strategy for NRAS mutant melanoma patients.

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The genetic and epigenetic basis of distinct melanoma types

Oba J., Woodman S.E.

Journal of Dermatology (Journal of Dermatology) 48 ( 7 ) 925 - 939 2021.07

Research paper (scientific journal), Joint Work, Lead author, Accepted, ISSN 03852407

Melanoma represents the deadliest skin cancer. Recent therapeutic developments, including targeted and immune therapies have revolutionized clinical management and improved patient outcome. This progress was achieved by rigorous molecular and functional studies followed by robust clinical trials. The identification of key genomic alterations and gene expression profiles have propelled the understanding of distinct characteristics within melanoma subtypes. The aim of this review is to summarize and highlight the main genetic and epigenetic findings of melanomas and highlight their pathological and therapeutic importance.

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RT-PCR screening tests for SARS-CoV-2 with saliva samples in asymptomatic people: Strategy to maintain social and economic activities while reducing the risk of spreading the virus

Oba J., Taniguchi H., Sato M., Takamatsu R., Morikawa S., Nakagawa T., Takaishi H., Saya H., Matsuo K., Nishihara H.

Keio Journal of Medicine (Keio Journal of Medicine) 70 ( 2 ) 35 - 43 2021.06

Research paper (scientific journal), Joint Work, Lead author, Accepted, ISSN 00229717

The year 2020 will be remembered for the coronavirus disease 2019 (COVID-19) pandemic, which continues to affect the whole world. Early and accurate identification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is fundamental to combat the disease. Among the current diagnostic tests, real-time reverse transcriptase–polymerase chain reaction (RT-qPCR) is the most reliable and frequently used method. Herein, we discuss the interpretation of RT-qPCR results relative to viral infectivity. Although nasopharyngeal swab samples are often used for RT-qPCR testing, they require collection by trained medical staff. Saliva samples are emerging as an inexpensive and efficient alternative for large-scale screening. Pooled-sample testing of saliva has been applied for mass screening of SARS-CoV-2 infection. Current policies recommend isolating people with borderline cycle threshold (Ct) values (35<Ct <40), despite these Ct values indicating minimal infection risk. We propose the new concept of a “social cut-off” Ct value and risk stratification based on the correlation of Ct with infectivity. We also describe the experience of RT-qPCR screening of saliva samples at our institution. It is important to implement a scientific approach to minimize viral transmission while allowing economic and social activities to continue.

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Elevated endogenous SDHA drives pathological metabolism in highly metastatic uveal melanoma

Chattopadhyay C., Oba J., Roszik J., Marszalek J.R., Chen K., Qi Y., Eterovic K., Gordon Robertson A., Burks J.K., McCannel T.A., Grimm E.A., Woodman S.E.

Investigative Ophthalmology and Visual Science (Investigative Ophthalmology and Visual Science) 60 ( 13 ) 4187 - 4195 2019.10

Research paper (scientific journal), Joint Work, Accepted, ISSN 01460404

PURPOSE. Metastatic uveal melanoma (UM) has a very poor prognosis and no effective therapy. Despite remarkable advances in treatment of cutaneous melanoma, UM remains recalcitrant to chemotherapy, small-molecule kinase inhibitors, and immune-based therapy. METHODS. We assessed two sets of oxidative phosphorylation (OxPhos) genes within 9858 tumors across 31 cancer types. An OxPhos inhibitor was used to characterize differential metabolic programming of highly metastatic monosomy 3 (M3) UM. Seahorse analysis and global metabolomics profiling were done to identify metabolic vulnerabilities. Analyses of UM TCGA data set were performed to determine expressions of key OxPhos effectors in M3 and non-M3 UM. We used targeted knockdown of succinate dehydrogenase A (SDHA) to determine the role of SDHA in M3 UM in conferring resistance to OxPhos inhibition. RESULTS. We identified UM to have among the highest median OxPhos levels and showed that M3 UM exhibits a distinct metabolic profile. M3 UM shows markedly low succinate levels and has highly increased levels of SDHA, the enzyme that couples the tricarboxylic acid cycle with OxPhos by oxidizing (lowering) succinate. We showed that SDHA-high M3 UM have elevated expression of key OxPhos molecules, exhibit abundant mitochondrial reserve respiratory capacity, and are resistant to OxPhos antagonism, which can be reversed by SDHA knockdown. CONCLUSIONS. Our study has identified a critical metabolic program within poor prognostic M3 UM. In addition to the heightened mitochondrial functional capacity due to elevated SDHA, M3 UM SDHA-high mediate resistance to therapy that is reversible with targeted treatment.

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Tyrosine Kinase Inhibitor and Immune Checkpoint Inhibitor Responses in KIT-Mutant Metastatic Melanoma

McKean M., Oba J., Ma J., Roth K.G., Wang W.L., Macedo M.P., Carapeto F.C.L., Haydu L.E., Siroy A.E., Vo P., Hong D.S., Eterovic A.K., Patel K.P., Bassett R.L., Grimm E.A., Lazar A.J., Woodman S.E.

Journal of Investigative Dermatology (Journal of Investigative Dermatology) 139 ( 3 ) 728 - 731 2019.03

Research paper (scientific journal), Joint Work, Accepted, ISSN 0022202X

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CD38-mediated immunosuppression as a mechanism of tumor cell escape from PD-1/PD-l1 blockade

Chen L., Diao L., Yang Y., Yi X., Rodriguez B.L., Li Y., Villalobos P.A., Cascone T., Liu X., Tan L., Lorenzi P.L., Huang A., Zhao Q., Peng D., Fradette J.J., Peng D.H., Ungewiss C., Roybal J., Tong P., Oba J., Skoulidis F., Peng W., Carter B.W., Gay C.M., Fan Y., Class C.A., Zhu J., Rodriguez-Canales J., Kawakami M., Byers L.A., Woodman S.E., Papadimitrakopoulou V.A., Dmitrovsky E., Wang J., Ullrich S.E., Wistuba I.I., Heymach J.V., Qin F.X.F., Gibbons D.L.

Cancer Discovery (Cancer Discovery) 8 ( 9 ) 1156 - 1175 2018.09

Research paper (scientific journal), Joint Work, Accepted, ISSN 21598274

Although treatment with immune checkpoint inhibitors provides promising benefit for patients with cancer, optimal use is encumbered by high resistance rates and requires a thorough understanding of resistance mechanisms. We observed that tumors treated with PD-1/PD-L1 blocking antibodies develop resistance through the upregulation of CD38, which is induced by all-trans retinoic acid and IFNβ in the tumor microenvironment. In vitro and in vivo studies demonstrate that CD38 inhibits CD8+ T-cell function via adenosine receptor signaling and that CD38 or adenosine receptor blockade are effective strategies to overcome the resistance. Large data sets of human tumors reveal expression of CD38 in a subset of tumors with high levels of basal or treatment-induced T-cell infiltration, where immune checkpoint therapies are thought to be most effective. These findings provide a novel mechanism of acquired resistance to immune checkpoint therapy and an opportunity to expand their efficacy in cancer treatment. SIGNIFICANCE: CD38 is a major mechanism of acquired resistance to PD-1/PD-L1 blockade, causing CD8+ T-cell suppression. Coinhibition of CD38 and PD-L1 improves antitumor immune response. Biomarker assessment in patient cohorts suggests that a combination strategy is applicable to a large percentage of patients in whom PD-1/PD-L1 blockade is currently indicated.

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Targeting the HGF/MET Axis counters primary resistance to KIT inhibition in KIT-mutant melanoma

Oba J., Kim S.H., Wang W.L., Macedo M.P., Carapeto F., McKean M.A., Van Arnam J., Eterovic A.K., Sen S., Kale C.R., Yu X., Haymaker C.L., Routbort M., Haydu L.E., Bernatchez C., Lazar A.J., Grimm E.A., Hong D.S., Woodman S.E.

JCO Precision Oncology (JCO Precision Oncology) 2 1 - 8 2018

Research paper (scientific journal), Joint Work, Accepted

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Building a versatile medical test system in a pandemic

Oba J., Toriya M., Matsuo K.

Impact 2023 (2), 42-44 (Science Impact Ltd) ( 2 ) 42 - 44 2023.04

Joint Work, Lead author

The COVID-19 pandemic was unprecedented and forced countries to organise and combine resources and develop coordinated responses. Temporary systems were established with the support of researchers and other stakeholders. Dr Junna Oba, Assistant Professor at the Department of Extended Intelligence for Medicine at Keio University School of Medicine (KUSM) is devising methodologies for developing adjustable temporary systems that are quick and efficient to build, apply and dissemble when emergency situations have passed. KUSM helped to respond to the COVID-19 crisis by collaborating with basic science researches to reinforce the PCR testing system in hospitals. Among those involved in this effort were Professor Masako Toriya of Keio University Global Research Institute (KGRI) and Professor Koichi Matsuo from the KUSM's Collaborative Research Resources group. The researchers built from scratch a workflow for effective testing and information sharing. Since this time, the team has been working to build a cooperative network, developing a novel approach to planning, analysing and recording various processes and strategies to address emergency situations that will be shared with the wider healthcare community and policy makers. The researchers used systems engineering methods to launch an unprecedented collaborative system that offers the ability to gain an overall picture of the interrelationships between departments that are working together on the diagnosis, treatment and management of COVID-19.

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Integrative analysis identifies four molecular and clinical subsets in uveal melanoma

Robertson AG, Shih J, Yau C, Gibb EA, Oba J, Mungall KL, Hess JM, Uzunangelov V, Walter V, Danilova L, Lichtenberg TM, Kucherlapati M, Kimes PK, Tang M, Penson A, Babur O, Akbani R, Bristow CA, Hoadley KA, Iype L, Chang MT, Cherniack AD, Benz C, Mills GB, Verhaak RGW, Griewank KG, Felau I, Zenklusen JC, Gershenwald JE, Schoenfield L, Lazar AJ, Abdel-Rahman MH, Roman-Roman S, Stern MH, Cebulla CM, Williams MD, Jager MJ, Coupland SE, Esmaeli B, Kandoth C, Woodman SE.

Cancer Cell 32 ( 2 ) 204 - 220 2017.08

Research paper (scientific journal), Joint Work, Accepted, ISSN 1535-6108

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Prediction of oral food challenge outcome using machine learning methods

T Arima, T Hirose, J Oba, T Ishikawa, Y Ichigi, M Ono, M Gondo, K Sugita, ...

Journal of Allergy and Clinical Immunology 155 (2), AB258 2025

Estimating copy number using next-generation sequencing to determine ERBB2 amplification status

K Nakamura, E Aimono, J Oba, H Hayashi, S Tanishima, T Hayashida, ...

Medical Oncology 38, 1-8 (Medical Oncology) 38 ( 4 ) 36 2021.04

Research paper (scientific journal), Accepted, ISSN 13570560

Assessing Erb-b2 receptor tyrosine kinase 2 (ERBB2) amplification status in breast and gastric cancer is necessary for deciding the best therapeutic strategy. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) are currently used for assessing protein levels and gene copy number (CN), respectively. The use of next-generation sequencing (NGS) to measure ERBB2 CN in breast cancer is approved by the United States Federal Drug Administration as a companion diagnostic. However, a CN of less than 8 is evaluated as “equivocal”, which means that some ERBB2 amplification cases diagnosed as “HER2 negative” might be false-negative cases. We reviewed the results of gene profiling targeting 160 cancer-related genes in breast (N = 90) and non-breast (N = 19) cancer tissue, and compared the ERBB2 CN results with the IHC/FISH scores. We obtained an estimated CN from the measured CN by factoring in the histological proportion of tumor cells and found that an ERBB2-estimated CN of 3.2 or higher was concordant with the combined IHC/FISH outcome in 98.4% (88/90) of breast cancer cases, while this was not always evident among non-breast cancer cases. Therefore, NGS-estimated ERBB2 CN could be considered a diagnostic test for anti-HER2 therapy after the completion of adequate prospective clinical trials.

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Pulmonary metastasis secondary to abiraterone-resistant prostate cancer with homozygous deletions of BRCA2: First Japanese case

Izawa M., Kosaka T., Nakamura K., Oba J., Hishida T., Hongo H., Mikami S., Nishihara H., Oya M.

IJU Case Reports (IJU Case Reports) 4 ( 1 ) 14 - 17 2021.01

Research paper (scientific journal), Accepted

Introduction: Most metastatic prostate cancers acquire the capacity for androgen-independent growth and become resistant to androgen deprivation therapy. A patient-focused treatment strategy is needed for aggressive castration-resistant prostate cancer. Case presentation: We report the case of a 62-year-old man who presented with prostatic adenocarcinoma who was treated by radiation and combined androgen blockade. After completion of first-line therapy, he was diagnosed with multiple metastatic castration-resistant prostate cancer in the lung. Second-line therapy with abiraterone acetate resulted in partial remission of the lung metastases. Thoracic surgery was performed to remove the single lung metastasis remaining. Next-generation sequencing of the specimens demonstrated homozygous loss of BRCA2. We note in this case a heterogeneous response to abiraterone acetate may be related to the somatic BRCA2 deletions. Conclusions: We present the first Japanese case of a metastatic abiraterone acetate-resistant castration-resistant prostate cancer accompanied by BRCA2 mutation.

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Defining ERBB2 amplification status by Next-Generation Sequencing

K Nakamura, E Aimono, J Oba, A Ueki, M Imai, E Yanagita, H Yamada, ...

CANCER SCIENCE 112, 320-320 2021

The quality of DNA extracted from FFPE tissue is a critical factor for successful gene profiling test

E Yanagita, H Yamada, R Takamatsu, R Matsuoka, E Aimono, ...

CANCER SCIENCE 112, 324-324 2021

The diagnostic value of genomic screening test for the cancer patients at the initial treatment phase

E Aimono, K Nakamura, E Yanagita, H Yamada, E Sasaki, H Hayashi, ...

CANCER SCIENCE 112, 521-521 2021

Pulmonary metastasis secondary to abiraterone‐resistant prostate cancer with homozygous deletions of BRCA2: first Japanese case

M Izawa, T Kosaka, K Nakamura, J Oba, T Hishida, H Hongo, S Mikami, ...

IJU Case Reports 4 (1), 14-17 2021

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