205 results on '"Shumpei Ishikawa"'
Search Results
2. Predicting lymph node recurrence in cT1‐2N0 tongue squamous cell carcinoma: collaboration between artificial intelligence and pathologists
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Masahiro Adachi, Tetsuro Taki, Motohiro Kojima, Naoya Sakamoto, Kazuto Matsuura, Ryuichi Hayashi, Keiji Tabuchi, Shumpei Ishikawa, Genichiro Ishii, and Shingo Sakashita
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tongue neoplasms ,lymphatic metastasis ,pathology ,artificial intelligence ,Pathology ,RB1-214 - Abstract
Abstract Researchers have attempted to identify the factors involved in lymph node recurrence in cT1‐2N0 tongue squamous cell carcinoma (SCC). However, studies combining histopathological and clinicopathological information in prediction models are limited. We aimed to develop a highly accurate lymph node recurrence prediction model for clinical stage T1‐2, N0 (cT1‐2N0) tongue SCC by integrating histopathological artificial intelligence (AI) with clinicopathological information. A dataset from 148 patients with cT1‐2N0 tongue SCC was divided into training and test sets. The prediction models were constructed using AI‐extracted information from whole slide images (WSIs), human‐assessed clinicopathological information, and both combined. Weakly supervised learning and machine learning algorithms were used for WSIs and clinicopathological information, respectively. The combination model utilised both algorithms. Highly predictive patches from the model were analysed for histopathological features. In the test set, the areas under the receiver operating characteristic (ROC) curve for the model using WSI, clinicopathological information, and both combined were 0.826, 0.835, and 0.991, respectively. The highest area under the ROC curve was achieved with the model combining WSI and clinicopathological factors. Histopathological feature analysis showed that highly predicted patches extracted from recurrence cases exhibited significantly more tumour cells, inflammatory cells, and muscle content compared with non‐recurrence cases. Moreover, patches with mixed inflammatory cells, tumour cells, and muscle were significantly more prevalent in recurrence versus non‐recurrence cases. The model integrating AI‐extracted histopathological and human‐assessed clinicopathological information demonstrated high accuracy in predicting lymph node recurrence in patients with cT1‐2N0 tongue SCC.
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- 2024
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3. Registered multi-device/staining histology image dataset for domain-agnostic machine learning models
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Mieko Ochi, Daisuke Komura, Takumi Onoyama, Koki Shinbo, Haruya Endo, Hiroto Odaka, Miwako Kakiuchi, Hiroto Katoh, Tetsuo Ushiku, and Shumpei Ishikawa
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Science - Abstract
Abstract Variations in color and texture of histopathology images are caused by differences in staining conditions and imaging devices between hospitals. These biases decrease the robustness of machine learning models exposed to out-of-domain data. To address this issue, we introduce a comprehensive histopathology image dataset named PathoLogy Images of Scanners and Mobile phones (PLISM). The dataset consisted of 46 human tissue types stained using 13 hematoxylin and eosin conditions and captured using 13 imaging devices. Precisely aligned image patches from different domains allowed for an accurate evaluation of color and texture properties in each domain. Variation in PLISM was assessed and found to be significantly diverse across various domains, particularly between whole-slide images and smartphones. Furthermore, we assessed the improvement in domain shift using a convolutional neural network pre-trained on PLISM. PLISM is a valuable resource that facilitates the precise evaluation of domain shifts in digital pathology and makes significant contributions towards the development of robust machine learning models that can effectively address challenges of domain shift in histological image analysis.
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- 2024
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4. Extracting interpretable features for pathologists using weakly supervised learning to predict p16 expression in oropharyngeal cancer
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Masahiro Adachi, Tetsuro Taki, Naoya Sakamoto, Motohiro Kojima, Akihiko Hirao, Kazuto Matsuura, Ryuichi Hayashi, Keiji Tabuchi, Shumpei Ishikawa, Genichiro Ishii, and Shingo Sakashita
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Medicine ,Science - Abstract
Abstract One drawback of existing artificial intelligence (AI)-based histopathological prediction models is the lack of interpretability. The objective of this study is to extract p16-positive oropharyngeal squamous cell carcinoma (OPSCC) features in a form that can be interpreted by pathologists using AI model. We constructed a model for predicting p16 expression using a dataset of whole-slide images from 114 OPSCC biopsy cases. We used the clustering-constrained attention-based multiple-instance learning (CLAM) model, a weakly supervised learning approach. To improve performance, we incorporated tumor annotation into the model (Annot-CLAM) and achieved the mean area under the receiver operating characteristic curve of 0.905. Utilizing the image patches on which the model focused, we examined the features of model interest via histopathologic morphological analysis and cycle-consistent adversarial network (CycleGAN) image translation. The histopathologic morphological analysis evaluated the histopathological characteristics of image patches, revealing significant differences in the numbers of nuclei, the perimeters of the nuclei, and the intercellular bridges between p16-negative and p16-positive image patches. By using the CycleGAN-converted images, we confirmed that the sizes and densities of nuclei are significantly converted. This novel approach improves interpretability in histopathological morphology-based AI models and contributes to the advancement of clinically valuable histopathological morphological features.
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- 2024
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5. SegRep: Mask-Supervised Learning for Segment Representation in Pathology Images
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Chichun Yang, Daisuke Komura, Mieko Ochi, Miwako Kakiuchi, Hiroto Katoh, Tetsuo Ushiku, and Shumpei Ishikawa
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Digital pathology ,feature extraction ,representation learning ,segmentation ,self-supervised learning ,Electrical engineering. Electronics. Nuclear engineering ,TK1-9971 - Abstract
In pathology, various tissue and cell components play diverse biological roles. The morphology of each component can vary markedly with differentiation status or pathological conditions, making it critical for understanding diseases. Traditional computational pathology methods typically employ patch-based feature extraction, which aggregates visual features across entire images. However, this approach does not differentiate between tissue types, limiting component analysis. To address this limitation, we introduce a novel concept in pathology image analysis, namely segment representation learning, and present an algorithm, SegRep, for this purpose. SegRep uses a unique dual-masking strategy that combines input masking and feature map masking. This approach effectively removes external influences for the targeted segment, identified via a segmentation model or manual annotation, allowing for the extraction of segment-specific feature representations. In addition, SegRep utilizes a self-supervised learning algorithm to achieve optimized segment representation. We evaluated SegRep’s efficacy in clustering and classification tasks using a dataset of human gastric cancer samples. The results demonstrate SegRep’s superior capability in extracting feature vectors that are highly specific to different pathology image segments. Compared with traditional methods, SegRep shows significant improvements in accuracy and specificity in both clustering and classification tasks. Segment representations obtained via SegRep can offer a more detailed and insightful perspective on computational pathology, paving the way for advanced applications in the field.
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- 2024
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6. Meningiomas in patients with neurofibromatosis type 2 predominantly comprise ‘immunogenic subtype’ tumours characterised by macrophage infiltration
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Yu Teranishi, Satoru Miyawaki, Masahiro Nakatochi, Atsushi Okano, Kenta Ohara, Hiroki Hongo, Daiichiro Ishigami, Yu Sakai, Daisuke Shimada, Shunsaku Takayanagi, Masako Ikemura, Daisuke Komura, Hiroto Katoh, Jun Mitsui, Shinichi Morishita, Tetsuo Ushiku, Shumpei Ishikawa, Hirofumi Nakatomi, and Nobuhito Saito
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Neurofibromatosis type 2 ,Meningioma ,Tumour microenvironment ,Immune infiltration ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Although recent molecular analyses revealed that sporadic meningiomas have various genetic, epigenetic, and transcriptomic profiles, meningioma in patients with neurofibromatosis type 2 (NF2) have not been fully elucidated. This study investigated meningiomas' clinical, histological, and molecular characteristics in NF2 patients. A long-term retrospective follow-up (13.5 ± 5.5 years) study involving total 159 meningiomas in 37 patients with NF2 was performed. Their characteristics were assessed using immunohistochemistry (IHC), bulk-RNA sequencing, and copy number analysis. All variables of meningiomas in patients with NF2 were compared with those in 189 sporadic NF2-altered meningiomas in 189 patients. Most meningiomas in NF2 patients were stable, and the mean annual growth rate was 1.0 ± 1.8 cm3/year. Twenty-eight meningiomas (17.6%) in 25 patients (43.1%) were resected during the follow-up period. WHO grade I meningiomas in patients with NF2 were more frequent than in sporadic NF2-altered meningiomas (92.9% vs. 80.9%). Transcriptomic analysis for patients with NF2/sporadic NF2-altered WHO grade I meningiomas (n = 14 vs. 15, respectively) showed that tumours in NF2 patients still had a higher immune response and immune cell infiltration than sporadic NF2-altered meningiomas. Furthermore, RNA-seq/IHC-derived immunophenotyping corroborated this enhanced immune response by identifying myeloid cell infiltration, particularly in macrophages. Clinical, histological, and transcriptomic analyses of meningiomas in patients with NF2 demonstrated that meningiomas in NF2 patients showed less aggressive behaviour than sporadic NF2-altered meningiomas and elicited a marked immune response by identifying myeloid cell infiltration, particularly of macrophages.
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- 2023
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7. 1027 scTCR/RNA-Seq identifiy two exhausted T cell subsets in neoantigen-specific CD8+ T cells
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Yukari Kobayashi, Kazuhiro Kakimi, Koji Nagaoka, Shumpei Ishikawa, Tomoko Saito, Kazuyoshi Takeda, Hiroto Katoh, and Yoshikazu Totsuka
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2023
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8. Stomach encyclopedia: Combined single-cell and spatial transcriptomics reveal cell diversity and homeostatic regulation of human stomach
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Ayumu Tsubosaka, Daisuke Komura, Miwako Kakiuchi, Hiroto Katoh, Takumi Onoyama, Asami Yamamoto, Hiroyuki Abe, Yasuyuki Seto, Tetsuo Ushiku, and Shumpei Ishikawa
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CP: Genomics ,Biology (General) ,QH301-705.5 - Abstract
Summary: The stomach is an important digestive organ with various biological functions. However, because of the complexity of its cellular and glandular composition, its precise cellular biology has yet to be elucidated. In this study, we conducted single-cell RNA sequencing (scRNA-seq) and subcellular-level spatial transcriptomics analysis of the human stomach and constructed the largest dataset to date: a stomach encyclopedia. This dataset consists of approximately 380,000 cells from scRNA-seq and the spatial transcriptome, enabling integrated analyses of transcriptional and spatial information of gastric and metaplastic cells. This analysis identified LEFTY1 as an uncharacterized stem cell marker, which was confirmed through lineage tracing analysis. A wide variety of cell-cell interactions between epithelial and stromal cells, including PDGFRA+BMP4+WNT5A+ fibroblasts, was highlighted in the developmental switch of intestinal metaplasia. Our extensive dataset will function as a fundamental resource in investigations of the stomach, including studies of development, aging, and carcinogenesis.
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- 2023
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9. Deep texture representation analysis for histopathological images
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Ranny Rahaningrum Herdiantoputri, Daisuke Komura, Kei Fujisaka, Tohru Ikeda, and Shumpei Ishikawa
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Cancer ,Microscopy ,Computer Sciences ,Science (General) ,Q1-390 - Abstract
Summary: Deep texture representations (DTRs) produced from a bilinear convolutional neural network allow objective quantification of tumor histopathology images effectively. They can be used for various analyses, including visualization of morphological correlation between histology images, content-based image retrieval (CBIR), and supervised learning. This protocol describes the simplified workflow to analyze DTRs from data preparation, visualization of the histological profile, and CBIR analysis, to supervised learning model development to predict the profile from histological images.For complete details on the use and execution of this protocol, please refer to Komura et al. (2022).1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.
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- 2023
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10. Clinical significance of NF2 alteration in grade I meningiomas revisited; prognostic impact integrated with extent of resection, tumour location, and Ki-67 index
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Yu Teranishi, Atsushi Okano, Satoru Miyawaki, Kenta Ohara, Daiichiro Ishigami, Hiroki Hongo, Shogo Dofuku, Hirokazu Takami, Jun Mitsui, Masako Ikemura, Daisuke Komura, Hiroto Katoh, Tetsuo Ushiku, Shumpei Ishikawa, Masahiro Shin, Hirofumi Nakatomi, and Nobuhito Saito
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Meningioma genomics ,WHO grade ,Tumor location ,Tumor prognosis ,Precision medicine ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract NF2 alteration is the most commonly–found genetic abnormality in meningiomas and is known to initiate events for aggressive-type meningiomas. Whereas the prognosis of meningiomas differs depending on their epigenomic/transcriptomic profile, the effect of NF2 alteration on the prognosis of benign meningiomas is not fully elucidated. This study aimed to probe the importance of NF2 alteration in prognosis of WHO grade I meningiomas. A long-term retrospective follow-up (5.3 ± 4.5 years) study involving 281 consecutive WHO grade I meningioma patients was performed. We assessed tumour recurrence in correlation with extent of resection (EOR), histopathological findings, tumour location, and NF2 alteration. “NF2 meningioma” was defined as meningiomas with presence of NF2 mutation and/or 22q loss. Overall, NF2 meningioma per se was not a predictor of prognosis in the whole cohort; however, it was a predictor of recurrence in supratentorial meningiomas, together with EOR and Ki-67. In a striking contrast, NF2 meningioma showed a better prognosis than non-NF2 meningioma in infratentorial lesion. Supratentorial NF2 meningiomas had higher Ki-67 and forkhead box protein M1 expression than those of others, possibly explaining the worse prognosis in this subtype. The combination of NF2 alteration, high Ki-67 and supratentorial location defines subgroup with the worst prognosis among WHO grade I meningiomas. Clinical connotation of NF2 alteration in terms of prognosis of WHO grade I meningioma differs in an opposite way between supratentorial and infratentorial tumors. Integrated anatomical, histopathological, and genomic classifications will provide the best follow-up schedule and proactive measures.
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- 2022
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11. Non-Helicobacter pylori Helicobacter (NHPH) positive gastric cancer
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Tomohiko Yasuda, Hyun Seok Lee, Su Youn Nam, Hiroto Katoh, Yuko Ishibashi, Somay Yamagata Murayama, Hidenori Matsui, Hiroki Masuda, Emiko Rimbara, Nobuyuki Sakurazawa, Hideyuki Suzuki, Hiroshi Yoshida, Yasuyuki Seto, Shumpei Ishikawa, Seong Woo Jeon, Masahiko Nakamura, and Sachiyo Nomura
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Medicine ,Science - Abstract
Abstract Genetic analysis and culturing techniques for gastric non-Helicobacter pylori Helicobacter (NHPH) are progressing. NHPH is reported to accompany nodular gastritis, gastric MALT lymphoma, and mild gastritis. However, only a few gastric cancer cases infected by NHPH have been reported. PCR analysis specific for NHPH and H. pylori was performed for DNA from gastric mucosa of 282 Korean gastric cancer patients, who were treated with endoscopic submucosal dissection. For more precise strain detection of NHPH, NHPH-positive mucosa was stained by immunohistochemistry specific for Helicobacter suis. The Cancer Genome Atlas (TCGA) classification was analyzed for these 3 gastric cancer sub-groups by in situ hybridization and immunohistochemistry. Among 281 patients, 3 patients (1.1%) were positive for NHPH. One patient (Patient 1) was also positive for H. pylori by PCR, another patient (Patient 3) was positive for serum IgG for H. pylori, and the other patient (Patient 2) had no evidence for H. pylori infection. Gastric mucosa of Patients 2 and 3 were positive for H. suis staining. All three NHPH-positive gastric cancers were located in the antrum, and belonged to the Chromosomal Instability Type of TCGA classification. Gastric NHPH can be a cause of gastric cancer, although likely with lower pathogenesis than H. pylori.
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- 2022
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12. Brainstem intraparenchymal schwannoma with genetic analysis: a case report and literature review
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Daiichiro Ishigami, Satoru Miyawaki, Hirofumi Nakatomi, Shunsaku Takayanagi, Yu Teranishi, Kenta Ohara, Hiroki Hongo, Shogo Dofuku, Taichi Kin, Hiroyuki Abe, Jun Mitsui, Daisuke Komura, Hiroto Katoh, Shumpei Ishikawa, and Nobuhito Saito
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Intraparenchymal schwannoma ,Oncology ,Genetics ,Case report ,Internal medicine ,RC31-1245 ,QH426-470 - Abstract
Abstract Background Schwannomas are neoplasms that typically arise from the myelin sheath of peripheral nerves and rarely originate within the brain parenchyma. Some case reports present schwannomas arising from the brainstem, but regrowth of the tumor and the efficacy of postoperative irradiation have not been examined. In addition, the genetic background of schwannomas arising from the brainstem has not been investigated. Case presentation A 21-year-old male presented with diplopia, dysphagia, and left-sided hemiparesis, dysesthesia, and ataxia. Intracranial imaging showed a heterogeneous mass with a cystic lesion in the pontomedullary junction. Since the tumor caused obstructive hydrocephalus, the patient underwent subtotal tumor resection. A histopathologic evaluation aided a diagnosis of brainstem intraparenchymal schwannoma. Gradual postoperative mass regrowth was recognized. Three-dimensional conformal radiotherapy was performed on the residual mass and surgical cavity. No tumor regrowth was observed 4 years after surgery. To investigate the genetic background of the tumor, target sequences for 36 genes, including NF2, SMARCB1, and LZTR1, and microsatellite analysis for loss of 22q did not show any somatic variants or 22q loss. Conclusions We suggest that brainstem schwannomas might differ from conventional schwannomas in their genetic background.
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- 2021
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13. Multi-tumor analysis of cancer-stroma interactomes of patient-derived xenografts unveils the unique homeostatic process in renal cell carcinomas
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Kuniyo Sueyoshi, Daisuke Komura, Hiroto Katoh, Asami Yamamoto, Takumi Onoyama, Tsuyoshi Chijiwa, Takayuki Isagawa, Mariko Tanaka, Hiroshi Suemizu, Masato Nakamura, Yohei Miyagi, Hiroyuki Aburatani, and Shumpei Ishikawa
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Cancer systems biology ,Cancer ,Science - Abstract
Summary: The patient-derived xenograft (PDX) model is a versatile tool used to study the tumor microenvironment (TME). However, limited studies have described multi-tumor PDX screening strategies to detect hub regulators during cancer-stroma interaction. Transcriptomes of cancer (human) and stroma (mouse) components of 70 PDX samples comprising 9 distinctive tumor types were analyzed in this study. PDX models recapitulated the original tumors' features, including tumor composition and putative signaling. Particularly, kidney renal clear cell carcinoma (KIRC) stood out, with altered hypoxia-related pathways and a high proportion of endothelial cells in the TME. Furthermore, an integrated analysis conducted to predict paracrine effectors in the KIRC cancer-to-stroma communication detected well-established soluble factors responsible for the hypoxia-related reaction and the so-far unestablished soluble factor, apelin (APLN). Subsequent experiments also supported the potential role of APLN in KIRC tumor progression. Therefore, this paper hereby provides an analytical workflow to find hub regulators in cancer-stroma interactions.
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- 2021
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14. Capturing the differences between humoral immunity in the normal and tumor environments from repertoire-seq of B-cell receptors using supervised machine learning
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Hiroki Konishi, Daisuke Komura, Hiroto Katoh, Shinichiro Atsumi, Hirotomo Koda, Asami Yamamoto, Yasuyuki Seto, Masashi Fukayama, Rui Yamaguchi, Seiya Imoto, and Shumpei Ishikawa
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B-cell receptor/immunoglobulin ,Cancer ,Machine learning ,Computer applications to medicine. Medical informatics ,R858-859.7 ,Biology (General) ,QH301-705.5 - Abstract
Abstract Background The recent success of immunotherapy in treating tumors has attracted increasing interest in research related to the adaptive immune system in the tumor microenvironment. Recent advances in next-generation sequencing technology enabled the sequencing of whole T-cell receptors (TCRs) and B-cell receptors (BCRs)/immunoglobulins (Igs) in the tumor microenvironment. Since BCRs/Igs in tumor tissues have high affinities for tumor-specific antigens, the patterns of their amino acid sequences and other sequence-independent features such as the number of somatic hypermutations (SHMs) may differ between the normal and tumor microenvironments. However, given the high diversity of BCRs/Igs and the rarity of recurrent sequences among individuals, it is far more difficult to capture such differences in BCR/Ig sequences than in TCR sequences. The aim of this study was to explore the possibility of discriminating BCRs/Igs in tumor and in normal tissues, by capturing these differences using supervised machine learning methods applied to RNA sequences of BCRs/Igs. Results RNA sequences of BCRs/Igs were obtained from matched normal and tumor specimens from 90 gastric cancer patients. BCR/Ig-features obtained in Rep-Seq were used to classify individual BCR/Ig sequences into normal or tumor classes. Different machine learning models using various features were constructed as well as gradient boosting machine (GBM) classifier combining these models. The results demonstrated that BCR/Ig sequences between normal and tumor microenvironments exhibit their differences. Next, by using a GBM trained to classify individual BCR/Ig sequences, we tried to classify sets of BCR/Ig sequences into normal or tumor classes. As a result, an area under the curve (AUC) value of 0.826 was achieved, suggesting that BCR/Ig repertoires have distinct sequence-level features in normal and tumor tissues. Conclusions To the best of our knowledge, this is the first study to show that BCR/Ig sequences derived from tumor and normal tissues have globally distinct patterns, and that these tissues can be effectively differentiated using BCR/Ig repertoires.
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- 2019
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15. High expression of olfactomedin-4 is correlated with chemoresistance and poor prognosis in pancreatic cancer.
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Ryotaro Ohkuma, Erica Yada, Shumpei Ishikawa, Daisuke Komura, Hidenobu Ishizaki, Koji Tamada, Yutaro Kubota, Kazuyuki Hamada, Hiroo Ishida, Yuya Hirasawa, Hirotsugu Ariizumi, Etsuko Satoh, Midori Shida, Makoto Watanabe, Rie Onoue, Kiyohiro Ando, Junji Tsurutani, Kiyoshi Yoshimura, Takehiko Yokobori, Tetsuro Sasada, Takeshi Aoki, Masahiko Murakami, Tomoko Norose, Nobuyuki Ohike, Masafumi Takimoto, Masahiko Izumizaki, Shinichi Kobayashi, Takuya Tsunoda, and Satoshi Wada
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Medicine ,Science - Abstract
Pancreatic cancer has an extremely poor prognosis, and identification of novel predictors of therapeutic efficacy and prognosis is urgently needed. Chemoresistance-related molecules are correlated with poor prognosis and may be effective targets for cancer treatment. Here, we aimed to identify novel molecules correlated with chemoresistance and poor prognosis in pancreatic cancer. We established 10 patient-derived xenograft (PDX) lines from patients with pancreatic cancer and performed next-generation sequencing (NGS) of tumor tissues from PDXs after treatment with standard drugs. We established a gene-transferred tumor cell line to express chemoresistance-related molecules and analyzed the chemoresistance of the established cell line against standard drugs. Finally, we performed immunohistochemical (IHC) analysis of chemoresistance-related molecules using 80 pancreatic cancer tissues. From NGS analysis, we identified olfactomedin-4 (OLFM4) as having high expression in the PDX group treated with anticancer drugs. In IHC analysis, OLFM4 expression was also high in PDXs administered anticancer drugs compared with that in untreated PDXs. Chemoresistance was observed by in vitro analysis of tumor cell lines with forced expression of OLFM4. In an assessment of tissue specimens from 80 patients with pancreatic cancer, Kaplan-Meier analysis showed that patients in the low OLFM4 expression group had a better survival rate than patients in the high OLFM4 expression group. Additionally, multivariate analysis showed that high expression of OLFM4 was an independent prognostic factor predicting poor outcomes. Overall, our study revealed that high expression of OLFM4 was involved in chemoresistance and was an independent prognostic factor in pancreatic cancer. OLFM4 may be a candidate therapeutic target in pancreatic cancer.
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- 2020
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16. Machine Learning Methods for Histopathological Image Analysis
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Daisuke Komura and Shumpei Ishikawa
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Biotechnology ,TP248.13-248.65 - Abstract
Abundant accumulation of digital histopathological images has led to the increased demand for their analysis, such as computer-aided diagnosis using machine learning techniques. However, digital pathological images and related tasks have some issues to be considered. In this mini-review, we introduce the application of digital pathological image analysis using machine learning algorithms, address some problems specific to such analysis, and propose possible solutions. Keywords: Histopathology, Deep learning, Machine learning, Whole slide images, Computer assisted diagnosis, Digital image analysis
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- 2018
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17. Immunogenetic Profiling for Gastric Cancers Identifies Sulfated Glycosaminoglycans as Major and Functional B Cell Antigens in Human Malignancies
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Hiroto Katoh, Daisuke Komura, Hiroki Konishi, Ryohei Suzuki, Asami Yamamoto, Miwako Kakiuchi, Reiko Sato, Tetsuo Ushiku, Shogo Yamamoto, Kenji Tatsuno, Takashi Oshima, Sachiyo Nomura, Yasuyuki Seto, Masashi Fukayama, Hiroyuki Aburatani, and Shumpei Ishikawa
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Biology (General) ,QH301-705.5 - Abstract
Summary: Recent successes in tumor immunotherapies have highlighted the importance of tumor immunity. However, most of the work conducted to date has been on T cell immunity, while the role of B cell immunity in cancer remains more elusive. In this study, immunogenetic repertoire profiling for tumor-infiltrating B and T cells in gastric cancers was carried out to help reveal the architecture of B cell immunity in cancer. Humoral immunity in cancer was shown to involve oligoclonal expansions of tumor-specific and private B cell repertoires. We find that B cell repertoires in cancer are shaped by somatic hypermutation (SHM) either with or without positive selection biases, the latter of which tended to be auto-reactive. Importantly, we identified sulfated glycosaminoglycans (GAGs) as major functional B cell antigens among gastric tumors. Furthermore, natural anti-sulfated GAG antibodies discovered in gastric cancer tissues showed robust growth-suppressive functions against a wide variety of human malignancies of various organs. : Katoh et al. profile immunoglobulin repertoires of tumor-infiltrating B cells, identifying sulfated glycosaminoglycan as a major functional B cell antigen in tumors. Repertoire profiling for tumor-infiltrating B cells may pave the way to the development of therapeutic antibodies. Keywords: repertoire sequence, immunogenetics, tumor immunity, tumor-infiltrating B cell, sulfated glycosaminoglycan, therapeutic antibody, gastric cancer
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- 2017
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18. Functional genomics screen with pooled shRNA library and gene expression profiling with extracts of Azadirachta indica identify potential pathways for therapeutic targets in head and neck squamous cell carcinoma
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Neeraja M. Krishnan, Hiroto Katoh, Vinayak Palve, Manisha Pareek, Reiko Sato, Shumpei Ishikawa, and Binay Panda
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Drug target ,Pooled shRNA screen ,Neem ,Gene expression ,HSF-1 ,TGF-β ,Medicine ,Biology (General) ,QH301-705.5 - Abstract
Tumor suppression by the extracts of Azadirachta indica (neem) works via anti-proliferation, cell cycle arrest, and apoptosis, demonstrated previously using cancer cell lines and live animal models. However, very little is known about the molecular targets and pathways that neem extracts and their associated compounds act through. Here, we address this using a genome-wide functional pooled shRNA screen on head and neck squamous cell carcinoma cell lines treated with crude neem leaf extracts, known for their anti-tumorigenic activity. We analyzed differences in global clonal sizes of the shRNA-infected cells cultured under no treatment and treatment with neem leaf extract conditions, assayed using next-generation sequencing. We found 225 genes affected the cancer cell growth in the shRNA-infected cells treated with neem extract. Pathway enrichment analyses of whole-genome gene expression data from cells temporally treated with neem extract revealed important roles played by the TGF-β pathway and HSF-1-related gene network. Our results indicate that neem extract affects various important molecular signaling pathways in head and neck cancer cells, some of which may be therapeutic targets for this devastating tumor.
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- 2019
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19. Viral loads correlate with upregulation of PD-L1 and worse patient prognosis in Epstein-Barr Virus-associated gastric carcinoma.
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Atsuhito Nakayama, Hiroyuki Abe, Akiko Kunita, Ruri Saito, Teru Kanda, Hiroharu Yamashita, Yasuyuki Seto, Shumpei Ishikawa, and Masashi Fukayama
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Medicine ,Science - Abstract
Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC), one of four major gastric cancer types, consists of clonal growth of EBV-infected epithelial cells. However, the significance of viral loads in each tumor cell has not been evaluated. EBV-DNA is stably maintained in episomal form in the nucleus of each cancer cell. To estimate EBV copy number per genome (EBV-CN), qPCR of viral EBNA1 and host GAPDH, standardized by Namalwa DNA (one copy/genome), was applied to the formalin-fixed paraffin embedded (FFPE) surgically resected EBVaGC specimens (n = 43) and EBVaGC cell lines (SNU-719 and NCC-24). In surgical specimens, the cancer cell ratio (CCR) was determined with image analysis, and EBV-CN was obtained by adjusting qPCR value with CCR. Fluorescent in situ hybridization (FISH) was also applied to the FFPE sections using the whole EBV-genome as a probe. In surgical specimens, EBV-CN obtained by qPCR/CCR was between 1.2 and 185 copies with a median of 9.9. EBV-CN of SNU-719 and NCC-24 was 42.0 and 1.1, respectively. A linear correlation was observed with qPCR/CCR data up to 20 copies/genome (40 signals/nucleus), the limit of FISH analysis. In addition, substantial variation in the number of EBV foci was observed. Based on qPCR/CCR, high EBV-CN (>10 copies) correlated with PD-L1 expression in cancer cells (P = 0.015), but not with other pathological indicators. Furthermore, EBVaGC with high EBV-CN showed worse disease-specific survival (P = 0.041). Our findings suggest that cancer cell viral loads may contribute to expression of the immune checkpoint molecule and promotion of cancer progression in EBVaGC.
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- 2019
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20. Tumor Content Chart-Assisted HER2/CEP17 Digital PCR Analysis of Gastric Cancer Biopsy Specimens.
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Keisuke Matsusaka, Shumpei Ishikawa, Atsuhito Nakayama, Tetsuo Ushiku, Aiko Nishimoto, Masayuki Urabe, Nobuyuki Kaneko, Akiko Kunita, Atsushi Kaneda, Hiroyuki Aburatani, Mitsuhiro Fujishiro, Yasuyuki Seto, and Masashi Fukayama
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Medicine ,Science - Abstract
Evaluating HER2 gene amplification is an essential component of therapeutic decision-making for advanced or metastatic gastric cancer. A simple method that is applicable to small, formalin-fixed, paraffin-embedded biopsy specimens is desirable as an adjunct to or as a substitute for currently used HER2 immunohistochemistry and in situ hybridization protocols. In this study, we developed a microfluidics-based digital PCR method for determining HER2 and chromosome 17 centromere (CEP17) copy numbers and estimating tumor content ratio (TCR). The HER2/CEP17 ratio is determined by three variables-TCR and absolute copy numbers of HER2 and CEP17-by examining tumor cells; only the ratio of the latter two can be obtained by digital PCR using the whole specimen without purifying tumor cells. TCR was determined by semi-automatic image analysis. We developed a Tumor Content chart, which is a plane of rectangular coordinates consisting of HER2/CEP17 digital PCR data and TCR that delineates amplified, non-amplified, and equivocal areas. By applying this method, 44 clinical gastric cancer biopsy samples were classified as amplified (n = 13), non-amplified (n = 25), or equivocal (n = 6). By comparison, 11 samples were positive, 11 were negative, and 22 were equivocally immunohistochemistry. Thus, our novel method reduced the number of equivocal samples from 22 to 6, thereby obviating the need for confirmation by fluorescence or dual-probe in situ hybridization to < 30% of cases. Tumor content chart-assisted digital PCR analysis is also applicable to multiple sites in surgically resected tissues. These results indicate that this analysis is a useful alternative to HER2 immunohistochemistry in gastric cancers that can serve as a basis for the automated evaluation of HER2 status.
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- 2016
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21. HER2 Heterogeneity Is Associated with Poor Survival in HER2-Positive Breast Cancer
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Mari Hosonaga, Yoshimi Arima, Oltea Sampetrean, Daisuke Komura, Ikuko Koya, Takashi Sasaki, Eiichi Sato, Hideyuki Okano, Jun Kudoh, Shumpei Ishikawa, Hideyuki Saya, and Takashi Ishikawa
- Subjects
HER2 ,heterogeneity ,breast cancer ,poor prognosis ,caspase-1 ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Intratumoral human epidermal growth factor receptor 2 (HER2) heterogeneity has been reported in 16–36% of HER2-positive breast cancer and its clinical impact is under discussion. We examined the biological effects of HER2-heterogeneity on mouse models and analyzed metastatic brains by RNA sequence analysis. A metastatic mouse model was developed using 231-Luc (triple negative cells) and 2 HER2-positive cell lines, namely, HER2-60 and HER2-90 which showed heterogeneous and monotonous HER2 expressions, respectively. Metastatic lesions developed in 3 weeks in all the mice injected with HER2-60 cells, and in 69% of the mice injected with HER2-90 and 87.5% of the mice injected with 231-Luc. The median survival days of mice injected with 231-Luc, HER2-60, and HER2-90 cells were 29 (n = 24), 24 (n = 22) and 30 (n = 13) days, respectively. RNA sequence analysis showed that CASP-1 and its related genes were significantly downregulated in metastatic brain tumors with HER2-60 cells. The low expression of caspase-1 could be a new prognostic biomarker for early relapse in HER2-positive breast cancer.
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- 2018
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22. Hunner-Type (Classic) Interstitial Cystitis: A Distinct Inflammatory Disorder Characterized by Pancystitis, with Frequent Expansion of Clonal B-Cells and Epithelial Denudation.
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Daichi Maeda, Yoshiyuki Akiyama, Teppei Morikawa, Akiko Kunita, Yasunori Ota, Hiroto Katoh, Aya Niimi, Akira Nomiya, Shumpei Ishikawa, Akiteru Goto, Yasuhiko Igawa, Masashi Fukayama, and Yukio Homma
- Subjects
Medicine ,Science - Abstract
Interstitial cystitis (IC) is a chronic bladder disease with urinary frequency, bladder discomfort or bladder pain of unknown etiology. Based on cystoscopic findings, patients with IC are classified as either Hunner-type/classic IC (HIC), presenting with a specific Hunner lesion, or non-Hunner-type IC (NHIC), presenting with no Hunner lesion, but post-hydrodistension mucosal bleeding. Inflammatory cell infiltration, composed predominantly of lymphocytes, plasma cells and epithelial denudation, has in the past been documented as a major pathological IC finding. However, the significance of the pathological evaluation of IC, especially with regard to the difference between HIC and NHIC, has been downplayed in recent years. In this study, we performed immunohistochemical quantification of infiltrating T-lymphocytes, B-lymphocytes and plasma cells, and measured the amount of residual epithelium in urinary bladder biopsy specimens taken from patients with HIC and NHIC, and those with no IC, using image analysis software. In addition, in situ hybridization of the light chains was performed to examine clonal B-cell expansion. Lymphoplasmacytic infiltration was significantly more severe in HIC specimens than in NHIC specimens (P
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- 2015
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23. Concurrent activation of acetylation and tri-methylation of H3K27 in a subset of hepatocellular carcinoma with aggressive behavior.
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Akimasa Hayashi, Naoko Yamauchi, Junji Shibahara, Hiroshi Kimura, Teppei Morikawa, Shumpei Ishikawa, Genta Nagae, Akihiro Nishi, Yoshihiro Sakamoto, Norihiro Kokudo, Hiroyuki Aburatani, and Masashi Fukayama
- Subjects
Medicine ,Science - Abstract
Analysis of acetylation and tri-methylation of the same residue of histone molecules might identify a subset of hepatocellular carcinoma (HCC) with aggressive behavior. In the present study, we examined acetylation and tri-methylation of lysine 27 on histone H3 (H3K27ac and H3K27me3, respectively) because these two modifications are known to exhibit opposite effects (enhancing and silencing) on gene expression. Neoplastic and non-neoplastic tissues from 198 HCC cases were immunostained with specific monoclonal antibodies against H3K27ac and H3K27me3. The stained tissues were evaluated by an image analyzing program to generate histological scores (H-scores, range 0-300), which were determined by multiplying the percentage of positive-stained cells with the classified immunohistochemical marker intensity (0-3). HCC tissues showed significantly higher H3K27ac (156.7±86.8) and H3K27me3 H-scores (151.8±78.1) compared with the background liver (40.3±33.0 and 64.7±45.6, respectively) (both P
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- 2014
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24. Quantitative analysis of viral load per haploid genome revealed the different biological features of Merkel cell polyomavirus infection in skin tumor.
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Satoshi Ota, Shumpei Ishikawa, Yutaka Takazawa, Akiteru Goto, Takeshi Fujii, Ken-ichi Ohashi, and Masashi Fukayama
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Medicine ,Science - Abstract
Merkel cell polyomavirus (MCPyV) has recently been identified in Merkel cell carcinoma (MCC), an aggressive cancer that occurs in sun-exposed skin. Conventional technologies, such as polymerase chain reaction (PCR) and immunohistochemistry, have produced conflicting results for MCPyV infections in non-MCC tumors. Therefore, we performed quantitative analyses of the MCPyV copy number in various skin tumor tissues, including MCC (n = 9) and other sun exposure-related skin tumors (basal cell carcinoma [BCC, n = 45], actinic keratosis [AK, n = 52], Bowen's disease [n = 34], seborrheic keratosis [n = 5], primary cutaneous anaplastic large-cell lymphoma [n = 5], malignant melanoma [n = 5], and melanocytic nevus [n = 6]). In a conventional PCR analysis, MCPyV DNA was detected in MCC (9 cases; 100%), BCC (1 case; 2%), and AK (3 cases; 6%). We then used digital PCR technology to estimate the absolute viral copy number per haploid human genome in these tissues. The viral copy number per haploid genome was estimated to be around 1 in most MCC tissues, and there were marked differences between the MCC (0.119-42.8) and AK (0.02-0.07) groups. PCR-positive BCC tissue showed a similar viral load as MCC tissue (0.662). Immunohistochemistry with a monoclonal antibody against the MCPyV T antigen (CM2B4) demonstrated positive nuclear localization in most of the high-viral-load tumor groups (8 of 9 MCC and 1 BCC), but not in the low-viral-load or PCR-negative tumor groups. These results demonstrated that MCPyV infection is possibly involved in a minority of sun-exposed skin tumors, including BCC and AK, and that these tumors display different modes of infection.
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- 2012
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25. DNA methylation profiling of embryonic stem cell differentiation into the three germ layers.
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Takayuki Isagawa, Genta Nagae, Nobuaki Shiraki, Takanori Fujita, Noriko Sato, Shumpei Ishikawa, Shoen Kume, and Hiroyuki Aburatani
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Medicine ,Science - Abstract
Embryogenesis is tightly regulated by multiple levels of epigenetic regulation such as DNA methylation, histone modification, and chromatin remodeling. DNA methylation patterns are erased in primordial germ cells and in the interval immediately following fertilization. Subsequent developmental reprogramming occurs by de novo methylation and demethylation. Variance in DNA methylation patterns between different cell types is not well understood. Here, using methylated DNA immunoprecipitation and tiling array technology, we have comprehensively analyzed DNA methylation patterns at proximal promoter regions in mouse embryonic stem (ES) cells, ES cell-derived early germ layers (ectoderm, endoderm and mesoderm) and four adult tissues (brain, liver, skeletal muscle and sperm). Most of the methylated regions are methylated across all three germ layers and in the three adult somatic tissues. This commonly methylated gene set is enriched in germ cell-associated genes that are generally transcriptionally inactive in somatic cells. We also compared DNA methylation patterns by global mapping of histone H3 lysine 4/27 trimethylation, and found that gain of DNA methylation correlates with loss of histone H3 lysine 4 trimethylation. Our combined findings indicate that differentiation of ES cells into the three germ layers is accompanied by an increased number of commonly methylated DNA regions and that these tissue-specific alterations in methylation occur for only a small number of genes. DNA methylation at the proximal promoter regions of commonly methylated genes thus appears to be an irreversible mark which functions to fix somatic lineage by repressing the transcription of germ cell-specific genes.
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- 2011
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26. Tumor DNA in Peritoneal Lavage as a Novel Biomarker for Predicting Peritoneal Recurrence in Patients With Gastric Cancer
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NORIO YUKAWA, TAKESHI YAMADA, TORU AOYAMA, TEKKAN WOO, KOJI UEDA, AKIHISA MASTUDA, KENTARO HARA, KEISUKE KAZAMA, HIROSHI TAMAGAWA, TSUTOMU SATO, TAKASHI OSHIMA, AKIHIRO SUZUKI, HIROYUKI ABURATANI, SHUMPEI ISHIKAWA, AYA SAITO, MUNETAKA MASUDA, HIROSHI YOSHIDA, and YASUSHI RINO
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Cancer Research ,Oncology ,General Medicine - Published
- 2023
27. Multiancestry genomic and transcriptomic analysis of gastric cancer
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Yasushi Totoki, Mihoko Saito-Adachi, Yuichi Shiraishi, Daisuke Komura, Hiromi Nakamura, Akihiro Suzuki, Kenji Tatsuno, Hirofumi Rokutan, Natsuko Hama, Shogo Yamamoto, Hanako Ono, Yasuhito Arai, Fumie Hosoda, Hiroto Katoh, Kenichi Chiba, Naoko Iida, Genta Nagae, Hiroki Ueda, Chen Shihang, Shigeki Sekine, Hiroyuki Abe, Sachiyo Nomura, Tetsuya Matsuura, Eiji Sakai, Takashi Ohshima, Yasushi Rino, Khay Guan Yeoh, Jimmy So, Kaushal Sanghvi, Richie Soong, Akihiko Fukagawa, Shinichi Yachida, Mamoru Kato, Yasuyuki Seto, Tetsuo Ushiku, Atsushi Nakajima, Hitoshi Katai, Patrick Tan, Shumpei Ishikawa, Hiroyuki Aburatani, and Tatsuhiro Shibata
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Genetics - Published
- 2023
28. Immune repertoire profiling for disease pathobiology
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Hiroto Katoh, Daisuke Komura, Genta Furuya, and Shumpei Ishikawa
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General Medicine ,Pathology and Forensic Medicine - Abstract
Lymphocytes consist of highly heterogeneous populations, each expressing a specific cell surface receptor corresponding to a particular antigen. Lymphocytes are both the cause and regulator of various diseases, including autoimmune/allergic diseases, lifestyle diseases, neurodegenerative diseases, and cancers. Recently, immune repertoire sequencing has attracted much attention because it helps obtain global profiles of the immune receptor sequences of infiltrating T and B cells in specimens. Immune repertoire sequencing not only helps deepen our understanding of the molecular mechanisms of immune-related pathology but also assists in discovering novel therapeutic modalities for diseases, thereby shedding colorful light on otherwise tiny monotonous cells when observed under a microscope. In this review article, we introduce and detail the background and methodology of immune repertoire sequencing and summarize recent scientific achievements in association with human diseases. Future perspectives on this genetic technique in the field of histopathological research will also be discussed.
- Published
- 2022
29. Nucleic acid–triggered tumoral immunity propagates <scp>pH</scp> ‐selective therapeutic antibodies through tumor‐driven epitope spreading
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Genta Furuya, Hiroto Katoh, Shinichiro Atsumi, Itaru Hashimoto, Daisuke Komura, Ryo Hatanaka, Shogo Senga, Shuto Hayashi, Shoji Akita, Hirofumi Matsumura, Akihiro Miura, Hideaki Mita, Makoto Nakakido, Satoru Nagatoishi, Akira Sugiyama, Ryohei Suzuki, Hiroki Konishi, Asami Yamamoto, Hiroyuki Abe, Nobuyoshi Hiraoka, Kazunori Aoki, Yasumasa Kato, Yasuyuki Seto, Chihoko Yoshimura, Kazutaka Miyadera, Kouhei Tsumoto, Tetsuo Ushiku, and Shumpei Ishikawa
- Subjects
Epitopes ,Cancer Research ,Oncology ,Nucleic Acids ,Neoplasms ,Antigens, Surface ,Humans ,General Medicine ,Antigens ,Hydrogen-Ion Concentration ,Antibodies - Abstract
Important roles of humoral tumor immunity are often pointed out; however, precise profiles of dominant antigens and developmental mechanisms remain elusive. We systematically investigated the humoral antigens of dominant intratumor immunoglobulin clones found in human cancers. We found that approximately half of the corresponding antigens were restricted to strongly and densely negatively charged polymers, resulting in simultaneous reactivities of the antibodies to both densely sulfated glycosaminoglycans (dsGAGs) and nucleic acids (NAs). These anti-dsGAG/NA antibodies matured and expanded via intratumoral immunological driving force of innate immunity via NAs. These human cancer-derived antibodies exhibited acidic pH-selective affinity across both antigens and showed specific reactivity to diverse spectrums of human tumor cells. The antibody-drug conjugate exerted therapeutic effects against multiple cancers in vivo by targeting cell surface dsGAG antigens. This study reveals that intratumoral immunological reactions propagate tumor-oriented immunoglobulin clones and demonstrates a new therapeutic modality for the universal treatment of human malignancies.
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- 2022
30. Pathological complete remission of relapsed tumor by <scp>photo‐activating</scp> antibody–mimetic drug conjugate treatment
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Yudai Kaneko, Kenzo Yamatsugu, Takefumi Yamashita, Kazuki Takahashi, Toshiya Tanaka, Sho Aki, Toshifumi Tatsumi, Takeshi Kawamura, Mai Miura, Masazumi Ishii, Kei Ohkubo, Tsuyoshi Osawa, Tatsuhiko Kodama, Shumpei Ishikawa, Masanobu Tsukagoshi, Michael Chansler, Akira Sugiyama, Motomu Kanai, and Hiroto Katoh
- Subjects
Mice ,Cancer Research ,Immunoconjugates ,Oncology ,Receptor, ErbB-2 ,Cell Line, Tumor ,Humans ,Animals ,General Medicine ,Antibodies - Abstract
Antibody-mimetic drug conjugate is a novel noncovalent conjugate consisting of an antibody-mimetic recognizing a target molecule on the cancer cell surface and low-molecular-weight payloads that kill the cancer cells. In this study, the efficacy of a photo-activating antibody-mimetic drug conjugate targeting HER2-expressing tumors was evaluated in mice, by using the affibody that recognize HER2 (Z
- Published
- 2022
31. KRAS mutation in intrahepatic cholangiocarcinoma: Linkage with metastasis‐free survival and reduced E‐cadherin expression
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Mariko Tanaka, Akiko Kunita, Makoto Yamagishi, Hiroto Katoh, Shumpei Ishikawa, Hiroyuki Yamamoto, Jun Abe, Junichi Arita, Kiyoshi Hasegawa, Tatsuhiro Shibata, and Tetsuo Ushiku
- Subjects
Cholangiocarcinoma ,Proto-Oncogene Proteins p21(ras) ,Bile Ducts, Intrahepatic ,Bile Duct Neoplasms ,Hepatology ,Antigens, CD ,Mutation ,Humans ,Interferons ,Cadherins ,Prognosis ,Disease-Free Survival - Abstract
Although KRAS mutations are the major driver of intrahepatic cholangiocarcinoma (ICC), their role remains unexplored. This study aimed to elucidate the prognostic effects, association with clinicopathologic characteristics and potent functions of KRAS mutations in ICC.A hundred and seven resected stage I-III ICCs were analysed for KRAS mutation status and its link with clinicopathological features. An independent validation cohort (n = 138) was included. In vitro analyses using KRAS-mutant ICC cell lines were performed.KRAS mutation was significantly associated with worse overall survival in stage I-III ICCs, which was validated in an independent cohort. Recurrence-free survival did not significantly differ between cases with and without KRAS mutations, but if limited to recurrence with extrahepatic metastasis, KRAS-mutant cases showed significantly worse distant metastasis-free survival than KRAS-wild cases showed. KRAS mutations were associated with frequent tumour budding with reduced E-cadherin expression. In vitro, KRAS depletion caused marked inhibition of cell growth and migration together with E-cadherin upregulation in KRAS-mutant ICC cells. The RNA-sequencing assay revealed that KRAS depletion caused MYC pathway downregulation and interferon pathway upregulation.Our observations suggest that KRAS mutations are associated with aggressive behaviour of ICC, especially the development of extrahepatic metastasis. Mutant KRAS is likely to change the adhesive status of ICC cells, affect the responsiveness of tumour cells to interferon immune signals, and consequently promote extrahepatic metastasis. KRAS mutation status, which predicts the prognoses of patients with ICC after surgical resection, is expected to help stratify patients better for individual postoperative treatment strategies.
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- 2022
32. Supplementary Table from Accumulation of Molecular Aberrations Distinctive to Hepatocellular Carcinoma Progression
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Hiroyuki Aburatani, Tadatoshi Takayama, Genta Nagae, Tatsuhiro Shibata, David A. Wheeler, Masahiko Sugitani, Chad J. Creighton, Kyle R. Covington, Shumpei Ishikawa, Hiroto Katoh, Takanori Fujita, Shiro Fukuda, Hiroki Ueda, Akimasa Hayashi, Shingo Tsuji, Claire Renard-Guillet, Kenji Tatsuno, Shogo Yamamoto, and Yutaka Midorikawa
- Abstract
Table S1 shows Clinical features. Table S2 shows Patient/sample information and NGS statistics. Table S3 shows Methylation status of CpG sites of WNT targets with CTNNB1 mutation. Table S4 shows Chromosomal aberrations.
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- 2023
33. Supplementary Data from Accumulation of Molecular Aberrations Distinctive to Hepatocellular Carcinoma Progression
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Hiroyuki Aburatani, Tadatoshi Takayama, Genta Nagae, Tatsuhiro Shibata, David A. Wheeler, Masahiko Sugitani, Chad J. Creighton, Kyle R. Covington, Shumpei Ishikawa, Hiroto Katoh, Takanori Fujita, Shiro Fukuda, Hiroki Ueda, Akimasa Hayashi, Shingo Tsuji, Claire Renard-Guillet, Kenji Tatsuno, Shogo Yamamoto, and Yutaka Midorikawa
- Abstract
Supplementary Figure legends
- Published
- 2023
34. Supplementary Figure from Accumulation of Molecular Aberrations Distinctive to Hepatocellular Carcinoma Progression
- Author
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Hiroyuki Aburatani, Tadatoshi Takayama, Genta Nagae, Tatsuhiro Shibata, David A. Wheeler, Masahiko Sugitani, Chad J. Creighton, Kyle R. Covington, Shumpei Ishikawa, Hiroto Katoh, Takanori Fujita, Shiro Fukuda, Hiroki Ueda, Akimasa Hayashi, Shingo Tsuji, Claire Renard-Guillet, Kenji Tatsuno, Shogo Yamamoto, and Yutaka Midorikawa
- Abstract
Figure S1 shows Histological findings of stepwise hepatocarcinogenesis and somatic substitution patterns. Figure S2 shows Activation of WNT targets. Figure S3 shows Homozygous deletion in 4q and 16q. Figure S4 shows Circos plot and transcription of the 5' portion of fusion genes that included TERT sequences. Figure S5 shows Upregulation mechanisms of TERT gene. Figure S6 shows Classification of HCC samples based on the methylation data.
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- 2023
35. Data from Accumulation of Molecular Aberrations Distinctive to Hepatocellular Carcinoma Progression
- Author
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Hiroyuki Aburatani, Tadatoshi Takayama, Genta Nagae, Tatsuhiro Shibata, David A. Wheeler, Masahiko Sugitani, Chad J. Creighton, Kyle R. Covington, Shumpei Ishikawa, Hiroto Katoh, Takanori Fujita, Shiro Fukuda, Hiroki Ueda, Akimasa Hayashi, Shingo Tsuji, Claire Renard-Guillet, Kenji Tatsuno, Shogo Yamamoto, and Yutaka Midorikawa
- Abstract
Cancer develops through the accumulation of genetic and epigenetic aberrations. To identify sequential molecular alterations that occur during the development of hepatocellular carcinoma (HCC), we compared 52 early and 108 overt HCC samples by genome sequencing. Gene mutations in the p53/RB1 pathway, WNT pathway, MLL protein family, SWI/SNF complexes, and AKT/PI3K pathway were common in HCC. In the early phase of all entities, TERT was the most frequently upregulated gene owing to diverse mechanisms. Despite frequent somatic mutations in driver genes, including CTNNB1 and TP53, early HCC was a separate molecular entity from overt HCC, as each had a distinct expression profile. Notably, WNT target genes were not activated in early HCC regardless of CTNNB1 mutation status because β-catenin did not translocate into the nucleus due to the E-cadherin/β-catenin complex at the membrane. Conversely, WNT targets were definitively upregulated in overt HCC, with CTNNB1 mutation associated with downregulation of CDH1 and hypomethylation of CpG islands in target genes. Similarly, cell-cycle genes downstream of the p53/RB pathway were upregulated only in overt HCC, with TP53 or RB1 gene mutations associated with chromosomal deletion of 4q or 16q. HCC was epigenetically distinguished into four subclasses: normal-like methylation, global-hypomethylation (favorable prognosis), stem-like methylation (poor prognosis), and CpG island methylation. These methylation statuses were globally maintained through HCC progression. Collectively, these data show that as HCC progresses, additional molecular events exclusive of driver gene mutations cooperatively contribute to transcriptional activation of downstream targets according to methylation status.Significance:In addition to driver gene mutations in the WNT and p53 pathways, further molecular events are required for aberrant transcriptional activation of these pathways as HCC progresses.
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- 2023
36. Supplementary Table 1 from Activation of DNA Methyltransferase 1 by EBV Latent Membrane Protein 2A Leads to Promoter Hypermethylation of PTEN Gene in Gastric Carcinoma
- Author
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Masashi Fukayama, Kenzo Takada, Takashi Sakatani, Takeo Nakaya, Teppei Morikawa, Shumpei Ishikawa, Aya Shinozaki, Tetsuo Ushiku, Noriko Murakami, Hiroshi Uozaki, and Rumi Hino
- Abstract
Supplementary Table 1 from Activation of DNA Methyltransferase 1 by EBV Latent Membrane Protein 2A Leads to Promoter Hypermethylation of PTEN Gene in Gastric Carcinoma
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- 2023
37. Data from Activation of DNA Methyltransferase 1 by EBV Latent Membrane Protein 2A Leads to Promoter Hypermethylation of PTEN Gene in Gastric Carcinoma
- Author
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Masashi Fukayama, Kenzo Takada, Takashi Sakatani, Takeo Nakaya, Teppei Morikawa, Shumpei Ishikawa, Aya Shinozaki, Tetsuo Ushiku, Noriko Murakami, Hiroshi Uozaki, and Rumi Hino
- Abstract
CpG island promoter methylation of tumor suppressor genes is one of the most characteristic abnormalities in EBV-associated gastric carcinoma (GC). Aberrant promoter methylation and expression loss of PTEN were evaluated in cancer tissues of GC by methylation-specific PCR and immunohistochemistry, respectively, showing that both abnormalities occurred concurrently in EBV-associated GC. PTEN abnormalities were reiterated in GC cell lines MKN-1 and MKN-7 infected with recombinant EBV, and DNA methyltransferase 1 (DNMT1) was commonly overexpressed in both cell lines. Stable and transient transfection systems in MKN-1 similarly showed that viral latent membrane protein 2A (LMP2A) up-regulated DNMT1, leading to an increase in methylation of the PTEN promoter. Importantly, the level of phosphorylated signal transducer and activator of transcription 3 (pSTAT3) increased in the nuclei of LMP2A-expressing GC cells, and knockdown of STAT3 counteracted LMP2A-mediated DNMT1 overexpression. Immunohistochemistry for both pSTAT3 and DNMT1 showed diffuse labeling in the nuclei of the cancer cells in GC tissues, especially in EBV-associated GC. Taken together, LMP2A induces the phosphorylation of STAT3, which activates DNMT1 transcription and causes PTEN expression loss through CpG island methylation of the PTEN promoter in EBV-associated GC. LMP2A plays an essential role in the epigenetic abnormalities in host stomach cells and in the development and maintenance of EBV-associated cancer. [Cancer Res 2009;69(7):2766–74]
- Published
- 2023
38. Analyzing Antibody Repertoire Using Next-Generation Sequencing and Machine Learning
- Author
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Shuto Hayashi and Shumpei Ishikawa
- Published
- 2022
39. Analyzing Antibody Repertoire Using Next-Generation Sequencing and Machine Learning
- Author
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Shuto, Hayashi and Shumpei, Ishikawa
- Subjects
Machine Learning ,High-Throughput Nucleotide Sequencing - Abstract
Advances in high-throughput sequencing technologies have enabled comprehensive sequencing of the immune repertoire. Since repertoire analysis can help to explain the relationship between the immune system and diseases, several methods have been developed for repertoire analysis. Here, using simulated and real-world datasets, we describe how to use DeepRC, a method that applies cutting-edge machine learning techniques.
- Published
- 2022
40. Genomic landscape of a mouse model of diffuse-type gastric adenocarcinoma
- Author
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Hiroto Katoh, Shinji Tanaka, Johji Inazawa, Shumpei Ishikawa, Shu Shimada, Itsuki Sugita, Daisuke Komura, and Menghua Zhang
- Subjects
Cancer Research ,Whole-genome sequence ,DNA Copy Number Variations ,Adenocarcinoma ,medicine.disease_cause ,CDH1 ,Mouse model ,Mice ,Surgical oncology ,Stomach Neoplasms ,Chromosome instability ,Conditional gene knockout ,Medicine ,Animals ,Humans ,Copy-number variation ,biology ,business.industry ,Gastroenterology ,Cancer ,General Medicine ,Genomics ,medicine.disease ,Disease Models, Animal ,Oncology ,Genomic Profile ,Cancer research ,biology.protein ,Original Article ,business ,Carcinogenesis ,Gastric cancer - Abstract
Background There is a need for a model of diffuse-type gastric cancer that captures the features of the disease, facilitates the study of its mechanisms, and aids the development of potential therapies. One such model may be Cdh1 and Trp53 double conditional knockout (DCKO) mice, which have histopathological features similar to those of human diffuse-type gastric cancer. However, a genomic profile of this mouse model has yet to be completed. Methods Whole-genome sequences of tumors from eight DCKO mice were analyzed and their molecular features were compared with those of human gastric adenocarcinoma. Results DCKO mice gastric cancers harbored single nucleotide variations and indel patterns comparable to those of human genomically stable gastric cancers, whereas their copy number variation fraction and ploidy were more similar to human chromosomal instability gastric cancers (perhaps due to Trp53 knockout). Copy number variations dominated changes in cancer-related genes in DCKO mice, with typical high-level amplifications observed for oncogenic drivers, e.g., Myc, Ccnd1, and Cdks, as well as gastrointestinal transcription factors, e.g., Gata4, Foxa1, and Sox9. Interestingly, frequent alterations in gastrointestinal transcription factors in DCKO mice indicated their potential role in tumorigenesis. Furthermore, mouse gastric cancer had a reproducible but smaller number of mutational signatures than human gastric cancer, including the potentially acid-related signature 17, indicating shared tumorigenic etiologies in humans and mice. Conclusions Cdh1/Trp53 DCKO mice have similar genomic features to those found in human gastric cancer; hence, this is a suitable model for further studies of diffuse-type gastric cancer mechanisms and therapies.
- Published
- 2021
41. ESDR201 - Role of keratinocyte proline-rich protein in psoriatic skin inflammation
- Author
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Shinichi Sato, Shumpei Ishikawa, Hirofumi Nakanishi, Ayumi Yoshizaki, Yoshifumi Ikeyama, Hayakazu Sumida, and Ai Matsuno
- Published
- 2022
42. Clonal germinal center B cells function as a niche for T-cell lymphoma
- Author
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Manabu Fujisawa, Tran B. Nguyen, Yoshiaki Abe, Yasuhito Suehara, Kota Fukumoto, Sakurako Suma, Kenichi Makishima, Chihiro Kaneko, Yen T.M. Nguyen, Kensuke Usuki, Kentaro Narita, Kosei Matsue, Naoya Nakamura, Shumpei Ishikawa, Fumihito Miura, Takashi Ito, Ayako Suzuki, Yutaka Suzuki, Seiya Mizuno, Satoru Takahashi, Shigeru Chiba, and Mamiko Sakata-Yanagimoto
- Subjects
Mice ,Immunoblastic Lymphadenopathy ,Immunology ,Humans ,Animals ,Mice, Transgenic ,Cell Biology ,Hematology ,T-Lymphocytes, Helper-Inducer ,Lymphoma, T-Cell ,Germinal Center ,Biochemistry - Abstract
Angioimmunoblastic T-cell lymphoma (AITL) is proposed to be initiated by age-related clonal hematopoiesis (ACH) with TET2 mutations, whereas the G17V RHOA mutation in immature cells with TET2 mutations promotes the development of T follicular helper (TFH)-like tumor cells. Here, we investigated the mechanism by which TET2-mutant immune cells enable AITL development using mouse models and human samples. Among the 2 mouse models, mice lacking Tet2 in all the blood cells (Mx-Cre × Tet2flox/flox × G17V RHOA transgenic mice) spontaneously developed AITL for approximately up to a year, while mice lacking Tet2 only in the T cells (Cd4-Cre × Tet2flox/flox × G17V RHOA transgenic mice) did not. Therefore, Tet2-deficient immune cells function as a niche for AITL development. Single-cell RNA-sequencing (scRNA-seq) of >50 000 cells from mouse and human AITL samples revealed significant expansion of aberrant B cells, exhibiting properties of activating light zone (LZ)-like and proliferative dark zone (DZ)-like germinal center B (GCB) cells. The GCB cells in AITL clonally evolved with recurrent mutations in genes related to core histones. In silico network analysis using scRNA-seq data identified Cd40–Cd40lg as a possible mediator of GCB and tumor cell cluster interactions. Treatment of AITL model mice with anti-Cd40lg inhibitory antibody prolonged survival. The genes expressed in aberrantly expanded GCB cells in murine tumors were also broadly expressed in the B-lineage cells of TET2-mutant human AITL. Therefore, ACH-derived GCB cells could undergo independent clonal evolution and support the tumorigenesis in AITL via the CD40–CD40LG axis.
- Published
- 2022
43. Single-Cell Transcriptome Analyses Reveal the Cell Diversity and Developmental Features of Human Gastric and Metaplastic Mucosa
- Author
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Ayumu Tsubosaka, Daisuke Komura, Hiroto Katoh, Miwako Kakiuchi, Takumi Onoyama, Asami Yamamoto, Hiroyuki Abe, Yasuyuki Seto, Tetsuo Ushiku, and Shumpei Ishikawa
- Abstract
The stomach is an important digestive organ with a variety of biological functions. However, due to the complexity of its cellular and glandular composition, the precise cellular biology has yet to be elucidated. In this study, we conducted single-cell RNA sequence analysis of the human stomach and constructed a 137,610-cell dataset, the largest cell atlas reported to date. By integrating this single-cell analysis with spatial cellular distribution analysis, we were able to clarify novel aspects of the developmental and tissue homeostatic ecosystems in the human stomach. We identified LEFTY1+ as a potential stem cell marker in both gastric and intestinal metaplastic glands. We also revealed skewed distribution patterns for PDGFRA+BMP4+WNT5A+ fibroblasts that play pivotal roles in, or even precede, the phenotypic changes from gastric to metaplastic mucosa. Our extensive dataset will function as a fundamental resource in investigations of the stomach, including studies on development, aging, and carcinogenesis.
- Published
- 2022
44. Beyond pathologist-level annotation of large-scale cancer histology for semantic segmentation using immunofluorescence restaining
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Daisuke Komura, Takumi Onoyama, Koki Shinbo, Hiroto Odaka, Minako Hayakawa, Mieko Ochi, Ranny Herdiantoputri, Kei Sakamoto, Hiroto Katoh, Tohru Ikeda, Tetsuo Ushiku, and Shumpei Ishikawa
- Abstract
Numerous cancer histopathology specimens have been collected and digitised as whole slide images over the past few decades. A comprehensive evaluation of the distribution of various cells in a section of tumour tissue can provide valuable information for understanding cancer and making accurate cancer diagnoses. Deep learning is one of the most suitable techniques to achieve these goals; however, the collection of large, unbiased training data has been a barrier to producing accurate segmentation models. Here, we developed a pipeline to generate SegPath, the largest annotation dataset that is over one order of magnitude larger than publicly available annotations, for the segmentation of haematoxylin and eosin (H&E)-stained sections for eight major cell types. The pipeline used H&E-stained sections that were destained and subsequently immunofluorescence-stained with carefully selected antibodies. The results showed that SegPath is comparable to, or significantly outperforms, conventional pathologist annotations. Moreover, we revealed that annotations by pathologists are biased toward typical morphologies; however, the model trained on SegPath can overcome this limitation. Our results provide foundational datasets for the histopathology machine learning community.
- Published
- 2022
45. Somatic GJA4 gain-of-function mutation in orbital cavernous venous malformations
- Author
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Hiroki Hongo, Satoru Miyawaki, Yu Teranishi, Jun Mitsui, Hiroto Katoh, Daisuke Komura, Kinya Tsubota, Takashi Matsukawa, Masakatsu Watanabe, Masakazu Kurita, Jun Yoshimura, Shogo Dofuku, Kenta Ohara, Daiichiro Ishigami, Atsushi Okano, Motoi Kato, Fumihiko Hakuno, Ayaka Takahashi, Akiko Kunita, Hiroyuki Ishiura, Masahiro Shin, Hirofumi Nakatomi, Toshitaka Nagao, Hiroshi Goto, Shin-Ichiro Takahashi, Tetsuo Ushiku, Shumpei Ishikawa, Mutsumi Okazaki, Shinichi Morishita, Shoji Tsuji, and Nobuhito Saito
- Subjects
Cancer Research ,Physiology ,Clinical Biochemistry - Abstract
Orbital cavernous venous malformation (OCVM) is a sporadic vascular anomaly of uncertain etiology characterized by abnormally dilated vascular channels. Here, we identify a somatic missense mutation, c.121G > T (p.Gly41Cys) in GJA4, which encodes a transmembrane protein that is a component of gap junctions and hemichannels in the vascular system, in OCVM tissues from 25/26 (96.2%) individuals with OCVM. GJA4 expression was detected in OCVM tissue including endothelial cells and the stroma, through immunohistochemistry. Within OCVM tissue, the mutation allele frequency was higher in endothelial cell-enriched fractions obtained using magnetic-activated cell sorting. Whole-cell voltage clamp analysis in Xenopus oocytes revealed that GJA4 c.121G > T (p.Gly41Cys) is a gain-of-function mutation that leads to the formation of a hyperactive hemichannel. Overexpression of the mutant protein in human umbilical vein endothelial cells led to a loss of cellular integrity, which was rescued by carbenoxolone, a non-specific gap junction/hemichannel inhibitor. Our data suggest that GJA4 c.121G > T (p.Gly41Cys) is a potential driver gene mutation for OCVM. We propose that hyperactive hemichannel plays a role in the development of this vascular phenotype.
- Published
- 2022
46. Restaining-based annotation for cancer histology segmentation to overcome annotation-related limitations among pathologists
- Author
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Daisuke Komura, Takumi Onoyama, Koki Shinbo, Hiroto Odaka, Minako Hayakawa, Mieko Ochi, Ranny Rahaningrum Herdiantoputri, Haruya Endo, Hiroto Katoh, Tohru Ikeda, Tetsuo Ushiku, and Shumpei Ishikawa
- Subjects
General Decision Sciences - Published
- 2023
47. Viola: a structural variant signature extractor with user-defined classifications
- Author
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Hiroki Dobashi, Shohei Matsuyama, Shumpei Ishikawa, Daisuke Komura, and Itsuki Sugita
- Subjects
Statistics and Probability ,Source code ,AcademicSubjects/SCI01060 ,Computer science ,media_common.quotation_subject ,User defined ,computer.software_genre ,Biochemistry ,Extractor ,Annotation ,Molecular Biology ,media_common ,Viola (butterfly) ,computer.programming_language ,biology ,business.industry ,Structural variant ,Pattern recognition ,Python (programming language) ,biology.organism_classification ,Genome Analysis ,Applications Notes ,Signature (logic) ,Computer Science Applications ,Computational Mathematics ,Computational Theory and Mathematics ,Artificial intelligence ,Data mining ,business ,computer - Abstract
Summary Here, we present Viola, a Python package that provides structural variant (SV; large scale genome DNA variations that can result in disease, e.g. cancer) signature analytical functions and utilities for custom SV classification, merging multi-SV-caller output files and SV annotation. We demonstrate that Viola can extract biologically meaningful SV signatures from publicly available SV data for cancer and we evaluate the computational time necessary for annotation of the data. Availability and implementation Viola is available on pip (https://pypi.org/project/Viola-SV/) and the source code is on GitHub (https://github.com/dermasugita/Viola-SV). Supplementary information Supplementary data are available at Bioinformatics online.
- Published
- 2021
48. Advanced deep learning applications in diagnostic pathology
- Author
-
Daisuke Komura and Shumpei Ishikawa
- Subjects
medicine.medical_specialty ,business.industry ,Computer science ,Deep learning ,medicine ,Whole slide image ,Medical physics ,Artificial intelligence ,business - Published
- 2021
49. Functional genomics screening identifies aspartyl-tRNA synthetase as a novel prognostic marker and a therapeutic target for gastric cancers
- Author
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Bin Liu, Hiroto Katoh, Daisuke Komura, Asami Yamamoto, Mieko Ochi, Takumi Onoyama, Hiroyuki Abe, Tetsuo Ushiku, Yasuyuki Seto, Jian Suo, and Shumpei Ishikawa
- Subjects
Stomach Neoplasms ,Cell Line, Tumor ,Gene Knockdown Techniques ,Aspartate-tRNA Ligase ,Humans ,Genomics ,RNA, Small Interfering ,Prognosis ,Early Detection of Cancer ,Pathology and Forensic Medicine - Abstract
Efficient molecular targeting therapies for most gastric cancers (GCs) are currently lacking, despite GC being one of the most frequent and often devastating malignancies worldwide. Thus, identification of novel therapeutic targets for GC is in high demand. Recent advancements of high-throughput nucleic acid synthesis methods combined with next-generation sequencing (NGS) platforms have made it feasible to conduct functional genomics screening using large-scale pooled lentiviral libraries aimed at discovering novel cancer therapeutic targets. In this study, we performed NGS-based functional genomics screening for human GC cell lines using an originally constructed 6,399 shRNA library targeting all 2,096 human metabolism genes. Our screening identified aspartyl-tRNA synthetase (DARS) as a possible candidate for a therapeutic target for GC. In-house tissue microarrays containing 346 cases of GC combined with public datasets showed that patients with high expression levels of DARS protein exhibited more advanced clinicopathologic parameters and a worse prognosis, specifically among diffuse-type GC patients. Both in vitro and in vivo experiments concretely evidenced that DARS inhibition achieved robust growth suppression of GC cells. Moreover, RNA sequencing of GC cell lines under shRNA-mediated DARS knockdown suggested that DARS inhibition exerts its effect through the inactivation of multiple p-ERK pathways. This MAPK-related growth suppression by DARS inhibition would also be applicable to other cancers; thus, it is warranted to investigate the expression and clinical significance of DARS in a wide spectrum of malignancies. Taken together, NGS-based high-throughput pooled lentiviral screening showed DARS as a novel prognostic marker and a promising therapeutic target for GC. © 2022 The Authors. The Journal of Pathology published by John Wileyamp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
- Published
- 2022
50. Gastric cancer and genomics: review of literature
- Author
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Takumi Onoyama, Shumpei Ishikawa, and Hajime Isomoto
- Subjects
Stomach Neoplasms ,Gastroenterology ,Tumor Microenvironment ,High-Throughput Nucleotide Sequencing ,Humans ,Genomics ,Neoplasm Recurrence, Local ,Precision Medicine - Abstract
Gastric cancer (GC) is a major health concern in many countries. GC is a heterogeneous disease stratified by histopathological differences. However, these variations are not used to determine GC management. Next-generation sequencing (NGS) technologies have become widely used, and cancer genomic analysis has recently revealed the relationships between various malignant tumors and genomic information. In 2014, studies using whole-exome sequencing (WES) and whole-genome sequencing (WGS) for GC revealed the entire structure of GC genomics. Genomics with NGS has been used to identify new therapeutic targets for GC. Moreover, personalized medicine to provide specific therapy for targets based on multiplex gene panel testing of tumor tissues has become of clinical use. Recently, immune checkpoint inhibitors (ICIs) have been used for GC treatment; however, their response rates are limited. To predict the anti-tumor effects of ICIs for GC and to select patients suitable for ICI treatment, genomics also provides informative data not only of tumors but also of tumor microenvironments, such as tumor-infiltrating lymphocytes. In therapeutic strategies for unresectable or recurrent malignant tumors, the target is not only the primary lesion but also metastatic lesions, and metastatic lesions are often resistant to chemotherapy. Unlike colorectal carcinoma, there is a heterogeneous status of genetic variants between the primary and metastatic lesions in GC. Liquid biopsy analysis is also helpful for predicting the genomic status of both primary and metastatic lesions. Genomics has become an indispensable tool for GC treatment and is expected to be further developed in the future.
- Published
- 2022
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