Long noncoding RNAs (lncRNAs) play pivotal roles in the development of human malignancies, though their involvement in oral squamous cell carcinoma (OSCC) remains incompletely understood. Using The Cancer Genome Atlas (TCGA) dataset, we analyzed expression of 7840 lncRNAs in primary head and neck squamous cell carcinoma (HNSCC) and found that upregulation of LINC02154 is associated with a poorer prognosis. LINC02154 knockdown in OSCC cell lines induced cell cycle arrest and apoptosis, and significantly attenuated tumor growth in vitro and in vivo. Notably, depletion of LINC02154 downregulated FOXM1, a master regulator of cell cycle-related genes. RNA pulldown and mass spectrometry analyses identified a series of proteins that could potentially interact with LINC02154, including HNRNPK and LRPPRC. HNRNPK stabilizes FOXM1 expression by interacting with the 3'-UTR of FOXM1 mRNA, which suggests LINC02154 and HNRNPK promote cell cycling by regulating FOXM1 expression. Additionally, LINC02154 positively regulates HNRNPK expression by inhibiting microRNAs targeting HNRPNK. Moreover, LINC02154 affects mitochondrial function by interacting with LRPPRC. Depletion of LINC02154 suppressed expression of mitochondrial genes, including MTCO1 and MTCO2, and inhibited mitochondrial respiratory function in OSCC cells. These results suggest that LINC02154 exerts its oncogenic effects by modulating the cell cycle and oxidative phosphorylation in OSCC, highlighting LINC02154 as a potential therapeutic target.
{"title":"LINC02154 promotes cell cycle and mitochondrial function in oral squamous cell carcinoma.","authors":"Takeshi Niinuma, Hiroshi Kitajima, Tatsuya Sato, Toshifumi Ogawa, Kazuya Ishiguro, Masahiro Kai, Eiichiro Yamamoto, Yui Hatanaka, Iyori Nojima, Mutsumi Toyota, Akira Yorozu, Shohei Sekiguchi, Noritsugu Tohse, Masato Furuhashi, Hiroshi Ohguro, Akihiro Miyazaki, Hiromu Suzuki","doi":"10.1111/cas.16379","DOIUrl":"https://doi.org/10.1111/cas.16379","url":null,"abstract":"<p><p>Long noncoding RNAs (lncRNAs) play pivotal roles in the development of human malignancies, though their involvement in oral squamous cell carcinoma (OSCC) remains incompletely understood. Using The Cancer Genome Atlas (TCGA) dataset, we analyzed expression of 7840 lncRNAs in primary head and neck squamous cell carcinoma (HNSCC) and found that upregulation of LINC02154 is associated with a poorer prognosis. LINC02154 knockdown in OSCC cell lines induced cell cycle arrest and apoptosis, and significantly attenuated tumor growth in vitro and in vivo. Notably, depletion of LINC02154 downregulated FOXM1, a master regulator of cell cycle-related genes. RNA pulldown and mass spectrometry analyses identified a series of proteins that could potentially interact with LINC02154, including HNRNPK and LRPPRC. HNRNPK stabilizes FOXM1 expression by interacting with the 3'-UTR of FOXM1 mRNA, which suggests LINC02154 and HNRNPK promote cell cycling by regulating FOXM1 expression. Additionally, LINC02154 positively regulates HNRNPK expression by inhibiting microRNAs targeting HNRPNK. Moreover, LINC02154 affects mitochondrial function by interacting with LRPPRC. Depletion of LINC02154 suppressed expression of mitochondrial genes, including MTCO1 and MTCO2, and inhibited mitochondrial respiratory function in OSCC cells. These results suggest that LINC02154 exerts its oncogenic effects by modulating the cell cycle and oxidative phosphorylation in OSCC, highlighting LINC02154 as a potential therapeutic target.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
We investigated the effectiveness and safety of nelarabine (NEL)-combined chemotherapy for newly diagnosed adult T-cell acute lymphoblastic leukemia (T-ALL) patients. We conducted a phase II trial, T-ALL213-O, where adult T-ALL patients aged 25 to 64 were treated by a regimen based on that used in our previous study, ALL202-O. The main modifications from ALL202-O to T-ALL213-O were as follows: (1) NEL-combined chemotherapy, instead of consolidation (C)1, was used for non-complete remission (CR) patients after induction therapy (IND)1 as IND2; (2) NEL treatments were inserted into C3 and C5 on day 29. Twenty-four patients were analyzed. Ten patients did not receive NEL treatment due to therapy termination prior to C3. Three-year event-free survival (EFS) was 70%, with 52% as the lower limit of its 90% confidence interval, which exceeded the threshold of 25%; thus, the study treatment was considered effective. The CR rates by IND1, IND2, and both were 75%, 100%, and 88%, respectively. The 5-year EFS and 5-year overall survival rates were 66% and 70%, respectively, with median follow-ups of 7.7 and 7.8 years. The addition of NEL improved the CR rate but not survival, compared with T-ALL patients in ALL202-O. Severe neuropathy after NEL administration was observed at a high frequency. Seven (50%) of 14 patients treated with NEL showed grade 3 peripheral neuropathy and/or gait disturbance. The neurotoxicity was considered stronger than that previously reported. Combination therapy of NEL at this dose and intensive multidrug chemotherapy is associated with a high risk of severe neurotoxicity (JALSG T-ALL213-O, UMIN000010642).
{"title":"Nelarabine-combined chemotherapy improves outcome of T-cell acute lymphoblastic leukemia but shows more severe neurotoxicity: JALSG T-ALL213-O.","authors":"Fumihiko Hayakawa, Naoki Mori, Kiyotoshi Imai, Yasuhisa Yokoyama, Yuna Katsuoka, Takeshi Saito, Tohru Murayama, Etsuko Yamazaki, Shinya Sato, Yoshiko Atsuta, Yuichi Ishikawa, Emiko Sakaida, Yoshihiro Hatta, Itaru Matsumura, Yasushi Miyazaki, Hitoshi Kiyoi","doi":"10.1111/cas.16405","DOIUrl":"https://doi.org/10.1111/cas.16405","url":null,"abstract":"<p><p>We investigated the effectiveness and safety of nelarabine (NEL)-combined chemotherapy for newly diagnosed adult T-cell acute lymphoblastic leukemia (T-ALL) patients. We conducted a phase II trial, T-ALL213-O, where adult T-ALL patients aged 25 to 64 were treated by a regimen based on that used in our previous study, ALL202-O. The main modifications from ALL202-O to T-ALL213-O were as follows: (1) NEL-combined chemotherapy, instead of consolidation (C)1, was used for non-complete remission (CR) patients after induction therapy (IND)1 as IND2; (2) NEL treatments were inserted into C3 and C5 on day 29. Twenty-four patients were analyzed. Ten patients did not receive NEL treatment due to therapy termination prior to C3. Three-year event-free survival (EFS) was 70%, with 52% as the lower limit of its 90% confidence interval, which exceeded the threshold of 25%; thus, the study treatment was considered effective. The CR rates by IND1, IND2, and both were 75%, 100%, and 88%, respectively. The 5-year EFS and 5-year overall survival rates were 66% and 70%, respectively, with median follow-ups of 7.7 and 7.8 years. The addition of NEL improved the CR rate but not survival, compared with T-ALL patients in ALL202-O. Severe neuropathy after NEL administration was observed at a high frequency. Seven (50%) of 14 patients treated with NEL showed grade 3 peripheral neuropathy and/or gait disturbance. The neurotoxicity was considered stronger than that previously reported. Combination therapy of NEL at this dose and intensive multidrug chemotherapy is associated with a high risk of severe neurotoxicity (JALSG T-ALL213-O, UMIN000010642).</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142688861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer stem cells aggregate to form clusters, which have enhanced stem-like properties and metastasis potential. However, the molecular mechanisms underlying the formation of cancer stem cell cluster-like structures with acquisition of stronger invasion and metastasis abilities remain unclear. Micropapillary carcinoma (MPC) is a subpopulation of small, merulioid, inverted, nonfibrous vascular clusters floating in the stroma present in a range of solid malignant tumors and characterized by frequent vascular/lymphatic vessel invasion and lymph node metastasis. Our results showed that these cell clusters exhibit a stem cell phenotype, supporting the premise that MPC may serve as a promising solid tumor model for studying invasion and metastasis of cancer stem cell clusters. In this review, we discuss the latest advances in MPC research and targeted therapy, focusing on analysis of their stem-like characteristics, mapping their multiomics characteristics, and elucidating the vascular and immune microenvironment of MPC. The existing MPC organoid model was employed to explore potential breakthroughs in targeted therapy and immunotherapy for cancer stem cell clusters.
{"title":"Micropapillary structure: A natural tumor collective invasion model with enhanced stem-like properties.","authors":"Sisi Li, Shuangshu Gao, Ling Qin, Caixia Ding, Jinghui Qu, Yifei Cui, Lixia Qiang, Shengjie Yin, Xiaoyu Zheng, Hongxue Meng","doi":"10.1111/cas.16396","DOIUrl":"https://doi.org/10.1111/cas.16396","url":null,"abstract":"<p><p>Cancer stem cells aggregate to form clusters, which have enhanced stem-like properties and metastasis potential. However, the molecular mechanisms underlying the formation of cancer stem cell cluster-like structures with acquisition of stronger invasion and metastasis abilities remain unclear. Micropapillary carcinoma (MPC) is a subpopulation of small, merulioid, inverted, nonfibrous vascular clusters floating in the stroma present in a range of solid malignant tumors and characterized by frequent vascular/lymphatic vessel invasion and lymph node metastasis. Our results showed that these cell clusters exhibit a stem cell phenotype, supporting the premise that MPC may serve as a promising solid tumor model for studying invasion and metastasis of cancer stem cell clusters. In this review, we discuss the latest advances in MPC research and targeted therapy, focusing on analysis of their stem-like characteristics, mapping their multiomics characteristics, and elucidating the vascular and immune microenvironment of MPC. The existing MPC organoid model was employed to explore potential breakthroughs in targeted therapy and immunotherapy for cancer stem cell clusters.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142683228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Adipose tissue and bacterial flora are involved in metabolism in the human body. However, the relationship between the two remains unclear. Recently, the presence of circulating bacterial DNAs has been reported. We previously reported the utility of bacterial DNA in serum extracellular vesicles (EVs) for diagnosing patients with renal cell carcinoma (RCC). In this study, we aimed to assess whether there is a correlation between bacterial DNA in serum EVs and inflammation in adipose tissue. We undertook 16S rRNA metagenomic analysis of bacterial DNA in serum EVs from 77 patients with RCC (the derivation cohort). We discovered that DNAs from Enterobacteriaceae, Polaromonas, and Coxiellaceae were highly expressed in patients with low Mayo adhesive probability (MAP) scores. A lower MAP score reflects a reduced risk of dense adipose tissue and adhesions. Additionally, we combined these bacterial DNAs to create the EPC (Enterobacteriaceae, Polaromonas, Coxiellaceae) index that predicts a MAP score of 0. Subsequently, we undertook 16S rRNA metagenomic analysis of bacterial DNA in serum EVs from 32 patients with RCC (the validation cohort). The EPC index could distinguish patients with low MAP scores from those with high MAP scores in the derivation (area under the curve [AUC], 0.76; sensitivity, 56%; specificity, 85%) and validation (AUC, 0.81; sensitivity, 100%; specificity, 62%) cohorts. These results suggest that bacterial DNA in serum EVs could reflect the inflammation of adherent perinephric fat around the kidney.
脂肪组织和细菌菌群都参与了人体的新陈代谢。然而,两者之间的关系仍不清楚。最近,有报道称存在循环细菌 DNA。我们曾报道过血清胞外囊泡(EVs)中的细菌 DNA 可用于诊断肾细胞癌(RCC)患者。在本研究中,我们旨在评估血清EVs中的细菌DNA与脂肪组织炎症之间是否存在相关性。我们对 77 名 RCC 患者(衍生队列)血清 EVs 中的细菌 DNA 进行了 16S rRNA 元基因组分析。我们发现,在梅奥粘附概率(MAP)评分较低的患者中,来自肠杆菌科、极单胞菌科和柯西菌科的DNA表达量较高。较低的 MAP 评分反映了致密脂肪组织和粘连风险的降低。随后,我们对 32 名 RCC 患者(验证队列)血清 EV 中的细菌 DNA 进行了 16S rRNA 元基因组分析。在推导队列(曲线下面积 [AUC],0.76;灵敏度,56%;特异度,85%)和验证队列(曲线下面积 [AUC],0.81;灵敏度,100%;特异度,62%)中,EPC 指数可以区分 MAP 评分低的患者和 MAP 评分高的患者。这些结果表明,血清 EV 中的细菌 DNA 可以反映肾脏周围附着的肾周脂肪的炎症情况。
{"title":"Bacterial information in serum extracellular vesicles reflects the inflammation of adherent perinephric fat.","authors":"Toshihiro Uemura, Atsunari Kawashima, Kentaro Jingushi, Daisuke Motooka, Takuro Saito, Nesrine Sassi, Yuki Horibe, Akinaru Yamamoto, Yutong Liu, Masaru Tani, Akihiro Yoshimura, Toshiki Oka, Yohei Okuda, Gaku Yamamichi, Yu Ishizuya, Yoshiyuki Yamamoto, Taigo Kato, Koji Hatano, Kazutake Tsujikawa, Hisashi Wada, Norio Nonomura","doi":"10.1111/cas.16410","DOIUrl":"https://doi.org/10.1111/cas.16410","url":null,"abstract":"<p><p>Adipose tissue and bacterial flora are involved in metabolism in the human body. However, the relationship between the two remains unclear. Recently, the presence of circulating bacterial DNAs has been reported. We previously reported the utility of bacterial DNA in serum extracellular vesicles (EVs) for diagnosing patients with renal cell carcinoma (RCC). In this study, we aimed to assess whether there is a correlation between bacterial DNA in serum EVs and inflammation in adipose tissue. We undertook 16S rRNA metagenomic analysis of bacterial DNA in serum EVs from 77 patients with RCC (the derivation cohort). We discovered that DNAs from Enterobacteriaceae, Polaromonas, and Coxiellaceae were highly expressed in patients with low Mayo adhesive probability (MAP) scores. A lower MAP score reflects a reduced risk of dense adipose tissue and adhesions. Additionally, we combined these bacterial DNAs to create the EPC (Enterobacteriaceae, Polaromonas, Coxiellaceae) index that predicts a MAP score of 0. Subsequently, we undertook 16S rRNA metagenomic analysis of bacterial DNA in serum EVs from 32 patients with RCC (the validation cohort). The EPC index could distinguish patients with low MAP scores from those with high MAP scores in the derivation (area under the curve [AUC], 0.76; sensitivity, 56%; specificity, 85%) and validation (AUC, 0.81; sensitivity, 100%; specificity, 62%) cohorts. These results suggest that bacterial DNA in serum EVs could reflect the inflammation of adherent perinephric fat around the kidney.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142683223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Genome-wide association studies (GWAS) statistically assess the association between tens of millions of genetic variants in the whole genome and a phenotype of interest. Genome-wide association studies enable the elucidation of polygenic inheritance of cancer, in which myriad low-penetrance genetic variants collectively contribute to a substantial proportion of the heritable susceptibility. In addition to the robust genotype-phenotype associations provided by GWAS, combining GWAS data with functional genomic datasets or sophisticated statistical genetic methods unlocks deeper insights. Integrating genotype and molecular phenotyping data facilitates functional characterization of GWAS association signals through molecular quantitative trait loci mapping and transcriptome-wide association studies. Furthermore, aggregating genome-wide polygenic signals, including subthreshold associations, enables one to estimate genetic correlations across diverse phenotypes and helps in clinical risk predictions by evaluating polygenic risk scores. In this review, we begin by summarizing the rationale for GWAS of cancer, introduce recent methodological updates in the GWAS-derived downstream analyses, and demonstrate their applications to GWAS of cancers.
{"title":"Leveraging genome-wide association studies to better understand the etiology of cancers.","authors":"Kyuto Sonehara, Yukinori Okada","doi":"10.1111/cas.16402","DOIUrl":"https://doi.org/10.1111/cas.16402","url":null,"abstract":"<p><p>Genome-wide association studies (GWAS) statistically assess the association between tens of millions of genetic variants in the whole genome and a phenotype of interest. Genome-wide association studies enable the elucidation of polygenic inheritance of cancer, in which myriad low-penetrance genetic variants collectively contribute to a substantial proportion of the heritable susceptibility. In addition to the robust genotype-phenotype associations provided by GWAS, combining GWAS data with functional genomic datasets or sophisticated statistical genetic methods unlocks deeper insights. Integrating genotype and molecular phenotyping data facilitates functional characterization of GWAS association signals through molecular quantitative trait loci mapping and transcriptome-wide association studies. Furthermore, aggregating genome-wide polygenic signals, including subthreshold associations, enables one to estimate genetic correlations across diverse phenotypes and helps in clinical risk predictions by evaluating polygenic risk scores. In this review, we begin by summarizing the rationale for GWAS of cancer, introduce recent methodological updates in the GWAS-derived downstream analyses, and demonstrate their applications to GWAS of cancers.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142677586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jun Mizuike, Kako Suzuki, Shu Tosaka, Yuta Kuze, Seiichiro Kobayashi, Makoto Nakashima, Koji Jimbo, Yasuhito Nannya, Yutaka Suzuki, Kaoru Uchimaru, Makoto Yamagishi
Human T-cell leukemia virus type 1 (HTLV-1) broadly impacts host genes, affecting the infected cell population and inducing the development of a disease with a poor prognosis, adult T-cell leukemia-lymphoma (ATL). This study aimed to provide a comprehensive epigenomic characterization of the infected cell population and evaluated the transcriptome and chromatin structures of peripheral blood cells in HTLV-1-infected individuals using RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin sequencing (ATAC-seq). The infected cells showed significant changes in gene expression patterns from the polyclonal stage and before ATL onset while demonstrating similarities to tumor-forming ATL cells. These similarities were a result of large-scale open chromatin changes, supporting the independent early formation of epigenomic aberrations as an underlying mechanism for later clonal propagation. This study also demonstrated that HTLV-1 Tax directly affects the host chromatin structure, thereby developing fundamental epigenomic characteristics. Several Tax target genes, including the RASGRP3-ERK pathway, were recognized, indicating an impact on signaling pathways. This genome-wide variability in chromatin structural property is a novel feature of HTLV-1 infection and may contribute to pathogenic mechanisms. In addition, it has crucial implications for better understanding the impact of HTLV-1 on the host genome and identifying novel therapeutic targets.
{"title":"Rewired chromatin structure and epigenetic gene dysregulation during HTLV-1 infection to leukemogenesis.","authors":"Jun Mizuike, Kako Suzuki, Shu Tosaka, Yuta Kuze, Seiichiro Kobayashi, Makoto Nakashima, Koji Jimbo, Yasuhito Nannya, Yutaka Suzuki, Kaoru Uchimaru, Makoto Yamagishi","doi":"10.1111/cas.16388","DOIUrl":"https://doi.org/10.1111/cas.16388","url":null,"abstract":"<p><p>Human T-cell leukemia virus type 1 (HTLV-1) broadly impacts host genes, affecting the infected cell population and inducing the development of a disease with a poor prognosis, adult T-cell leukemia-lymphoma (ATL). This study aimed to provide a comprehensive epigenomic characterization of the infected cell population and evaluated the transcriptome and chromatin structures of peripheral blood cells in HTLV-1-infected individuals using RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin sequencing (ATAC-seq). The infected cells showed significant changes in gene expression patterns from the polyclonal stage and before ATL onset while demonstrating similarities to tumor-forming ATL cells. These similarities were a result of large-scale open chromatin changes, supporting the independent early formation of epigenomic aberrations as an underlying mechanism for later clonal propagation. This study also demonstrated that HTLV-1 Tax directly affects the host chromatin structure, thereby developing fundamental epigenomic characteristics. Several Tax target genes, including the RASGRP3-ERK pathway, were recognized, indicating an impact on signaling pathways. This genome-wide variability in chromatin structural property is a novel feature of HTLV-1 infection and may contribute to pathogenic mechanisms. In addition, it has crucial implications for better understanding the impact of HTLV-1 on the host genome and identifying novel therapeutic targets.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142677587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pulmonary pleomorphic carcinoma (PC) is a rare non-small-cell lung carcinoma (NSCLC) with a poor prognosis, characterized by tumor necrosis (TN). NETosis is a form of neutrophil-specific cell death, which is morphologically characterized by prominent neutrophil infiltration and cell detritus in the necrotic foci. Seventy-six patients with pulmonary PC who underwent complete resection were enrolled. Tumor necrosis was evaluated using digitally scanned resected specimens. The regions of NETosis were quantified using citrullinated histone H3 (citH3)- and myeloperoxidase-positive regions. We examined the association between the NETosis area and the prognostic outcomes and assessed the correlation between the NETosis area and systemic inflammation. Tumor necrosis was observed in 70 patients (92%). In all the cases, the TN region was accompanied by a citH3-positive region. The patients with high NETosis area (n = 54) had significantly shorter overall survival than those with low NETosis area (n = 16) (p = 0.013). Furthermore, a high NETosis area was an independent poor prognostic factor in the multivariate analyses. Systemic inflammatory markers, including C-reactive protein (CRP), CRP-to-albumin ratio, and neutrophil-to-lymphocyte ratio, were significantly higher in patients with high NETosis area than in those with low NETosis area. Furthermore, the levels of these inflammatory markers were significantly decreased postsurgery. This study shows that in surgically resected pulmonary PC, patients with high NETosis areas have higher systemic inflammation and worse prognosis.
{"title":"NETosis in pulmonary pleomorphic carcinoma.","authors":"Hajime Oi, Tetsuro Taki, Takashi Kuroe, Naoya Sakamoto, Shingo Sakashita, Motohiro Kojima, Eri Sugiyama, Shigeki Umemura, Tetsuya Sakai, Hiroki Izumi, Yoshitaka Zenke, Shingo Matsumoto, Kiyotaka Yoh, Makoto Ishii, Masahiro Tsuboi, Koichi Goto, Genichiro Ishii","doi":"10.1111/cas.16332","DOIUrl":"https://doi.org/10.1111/cas.16332","url":null,"abstract":"<p><p>Pulmonary pleomorphic carcinoma (PC) is a rare non-small-cell lung carcinoma (NSCLC) with a poor prognosis, characterized by tumor necrosis (TN). NETosis is a form of neutrophil-specific cell death, which is morphologically characterized by prominent neutrophil infiltration and cell detritus in the necrotic foci. Seventy-six patients with pulmonary PC who underwent complete resection were enrolled. Tumor necrosis was evaluated using digitally scanned resected specimens. The regions of NETosis were quantified using citrullinated histone H3 (citH3)- and myeloperoxidase-positive regions. We examined the association between the NETosis area and the prognostic outcomes and assessed the correlation between the NETosis area and systemic inflammation. Tumor necrosis was observed in 70 patients (92%). In all the cases, the TN region was accompanied by a citH3-positive region. The patients with high NETosis area (n = 54) had significantly shorter overall survival than those with low NETosis area (n = 16) (p = 0.013). Furthermore, a high NETosis area was an independent poor prognostic factor in the multivariate analyses. Systemic inflammatory markers, including C-reactive protein (CRP), CRP-to-albumin ratio, and neutrophil-to-lymphocyte ratio, were significantly higher in patients with high NETosis area than in those with low NETosis area. Furthermore, the levels of these inflammatory markers were significantly decreased postsurgery. This study shows that in surgically resected pulmonary PC, patients with high NETosis areas have higher systemic inflammation and worse prognosis.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142649137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The expectations for artificial intelligence (AI) technology have increased considerably in recent years, mainly due to the emergence of deep learning. At present, AI technology is being used for various purposes and has brought about change in society. In particular, the rapid development of generative AI technology, exemplified by ChatGPT, has amplified the societal impact of AI. The medical field is no exception, with a wide range of AI technologies being introduced for basic and applied research. Further, AI-equipped software as a medical device (AI-SaMD) is also being approved by regulatory bodies. Combined with the advent of big data, data-driven research utilizing AI is actively pursued. Nevertheless, while AI technology has great potential, it also presents many challenges that require careful consideration. In this review, we introduce the current status of AI-based cancer research, especially from the perspective of clinical application, and discuss the associated challenges and future directions, with the aim of helping to promote cancer research that utilizes effective AI technology.
{"title":"Current status and future direction of cancer research using artificial intelligence for clinical application.","authors":"Ryuji Hamamoto, Masaaki Komatsu, Masayoshi Yamada, Kazuma Kobayashi, Masamichi Takahashi, Mototaka Miyake, Shunichi Jinnai, Takafumi Koyama, Nobuji Kouno, Hidenori Machino, Satoshi Takahashi, Ken Asada, Naonori Ueda, Syuzo Kaneko","doi":"10.1111/cas.16395","DOIUrl":"10.1111/cas.16395","url":null,"abstract":"<p><p>The expectations for artificial intelligence (AI) technology have increased considerably in recent years, mainly due to the emergence of deep learning. At present, AI technology is being used for various purposes and has brought about change in society. In particular, the rapid development of generative AI technology, exemplified by ChatGPT, has amplified the societal impact of AI. The medical field is no exception, with a wide range of AI technologies being introduced for basic and applied research. Further, AI-equipped software as a medical device (AI-SaMD) is also being approved by regulatory bodies. Combined with the advent of big data, data-driven research utilizing AI is actively pursued. Nevertheless, while AI technology has great potential, it also presents many challenges that require careful consideration. In this review, we introduce the current status of AI-based cancer research, especially from the perspective of clinical application, and discuss the associated challenges and future directions, with the aim of helping to promote cancer research that utilizes effective AI technology.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Geng Yan, Gao Mingyang, Shi Wei, Liang Hongping, Qin Liyuan, Liu Ailan, Kong Xiaomei, Zhao Huilan, Zhao Juanjuan, Qiang Yan
Leukemia is highly heterogeneous, meaning that different types of leukemia require different treatments and have different prognoses. Current clinical diagnostic and typing tests are complex and time-consuming. In particular, all of these tests rely on bone marrow aspiration, which is invasive and leads to poor patient compliance, exacerbating treatment delays. Morphological analysis of peripheral blood cells (PBC) is still primarily used to distinguish between benign and malignant hematologic disorders, but it remains a challenge to diagnose and type these diseases solely by direct observation of peripheral blood(PB) smears by human experts. In this study, we apply a segmentation-based enhanced residual network that uses progressive multigranularity training with jigsaw patches. It is trained on a self-built annotated dataset of 21,208 images from 237 patients, including five types of benign white blood cells(WBCs) and eight types of leukemic cells. The network is not only able to discriminate between benign and malignant cells, but also to typify leukemia using a single peripheral blood cell. The network effectively differentiated acute promyelocytic leukemia (APL) from other types of acute myeloid leukemia (non-APL), achieving a precision rate of 89.34%, a recall rate of 97.37%, and an F1 score of 93.18% for APL. In contrast, for non-APL cases, the model achieved a precision rate of 92.86%, but a recall rate of 74.63% and an F1 score of 82.75%. In addition, the model discriminates acute lymphoblastic leukemia(ALL) with the Ph chromosome from those without. This approach could improve patient compliance and enable faster and more accurate typing of leukemias for early diagnosis and treatment to improve survival.
{"title":"Diagnosis and typing of leukemia using a single peripheral blood cell through deep learning.","authors":"Geng Yan, Gao Mingyang, Shi Wei, Liang Hongping, Qin Liyuan, Liu Ailan, Kong Xiaomei, Zhao Huilan, Zhao Juanjuan, Qiang Yan","doi":"10.1111/cas.16374","DOIUrl":"10.1111/cas.16374","url":null,"abstract":"<p><p>Leukemia is highly heterogeneous, meaning that different types of leukemia require different treatments and have different prognoses. Current clinical diagnostic and typing tests are complex and time-consuming. In particular, all of these tests rely on bone marrow aspiration, which is invasive and leads to poor patient compliance, exacerbating treatment delays. Morphological analysis of peripheral blood cells (PBC) is still primarily used to distinguish between benign and malignant hematologic disorders, but it remains a challenge to diagnose and type these diseases solely by direct observation of peripheral blood(PB) smears by human experts. In this study, we apply a segmentation-based enhanced residual network that uses progressive multigranularity training with jigsaw patches. It is trained on a self-built annotated dataset of 21,208 images from 237 patients, including five types of benign white blood cells(WBCs) and eight types of leukemic cells. The network is not only able to discriminate between benign and malignant cells, but also to typify leukemia using a single peripheral blood cell. The network effectively differentiated acute promyelocytic leukemia (APL) from other types of acute myeloid leukemia (non-APL), achieving a precision rate of 89.34%, a recall rate of 97.37%, and an F1 score of 93.18% for APL. In contrast, for non-APL cases, the model achieved a precision rate of 92.86%, but a recall rate of 74.63% and an F1 score of 82.75%. In addition, the model discriminates acute lymphoblastic leukemia(ALL) with the Ph chromosome from those without. This approach could improve patient compliance and enable faster and more accurate typing of leukemias for early diagnosis and treatment to improve survival.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142649067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Multiple myeloma (MM) cells and osteoclasts (OCs) activate with each other to cause drug resistance. Human Th1-like Vγ9Vδ2 (γδ) T cells, important effectors against tumors, can be expanded and activated ex vivo by the aminobisphosphonate zoledronic acid in combination with IL-2. We previously reported that the expanded γδ T cells effectively targeted and killed OCs as well as MM cells. Because the expanded γδ T cells expressed CD16 on their surface, we investigated the utilization of the expanded γδ T cells for antibody-dependent cellular cytotoxicity (ADCC). Although the expanded γδ T cells alone induced cell death in MM cell lines, the addition of the anti-SLAMF7 monoclonal antibody elotuzumab (ELO) further enhanced their cytotoxic activity only against SLAMF7-expressing MM cell lines and primary MM cells. Intriguingly, ELO was also able to enhance γδ T cell-induced cell death against OCs cultured alone, and against both MM cells and OCs in their coculture settings. SLAMF7 was found to be highly expressed in OCs differentiated in vitro from monocytes by receptor activator of nuclear factor-κ B ligand and M-CSF, although monocytes only marginally expressed SLAMF7. These results demonstrate that SLAMF7 is highly expressed in both MM cells and OCs, and that the ex vivo-expanded γδ T cells can exert ELO-mediated ADCC against SLAMF7-expressing MM cells and OCs besides their direct cytotoxic activity. Further study is warranted for the innovative utilization of γδ T cells.
多发性骨髓瘤(MM)细胞和破骨细胞(OCs)相互激活,导致耐药性。人类Th1样Vγ9Vδ2 (γδ)T细胞是抗肿瘤的重要效应因子,可以通过氨基双膦酸类唑来膦酸与IL-2联合使用来扩增和活化体内Th1样Vγ9Vδ2 (γδ)T细胞。我们以前曾报道过,扩增的γδT细胞能有效地靶向杀伤OC和MM细胞。由于扩增的γδT细胞表面表达CD16,我们研究了扩增的γδT细胞对抗体依赖性细胞毒性(ADCC)的利用。虽然扩增的γδT细胞能单独诱导MM细胞系的细胞死亡,但加入抗SLAMF7单克隆抗体艾洛妥珠单抗(ELO)后,它们仅对表达SLAMF7的MM细胞系和原代MM细胞的细胞毒活性进一步增强。耐人寻味的是,ELO 还能增强γδ T 细胞诱导的细胞对单独培养的 OC 的死亡,以及对 MM 细胞和共培养环境中的 OC 的死亡。研究发现,SLAMF7 在体外由单核细胞通过核因子κ B 受体激活剂配体和 M-CSF 分化而成的 OCs 中高度表达,而单核细胞仅少量表达 SLAMF7。这些结果表明,SLAMF7 在 MM 细胞和 OC 中都有高表达,体内扩增的 γδ T 细胞除了直接的细胞毒活性外,还能对表达 SLAMF7 的 MM 细胞和 OC 发挥 ELO 介导的 ADCC 作用。对γδT细胞的创新利用还需要进一步研究。
{"title":"Elotuzumab-mediated ADCC with Th1-like Vγ9Vδ2 T cells to disrupt myeloma-osteoclast interaction.","authors":"Yusuke Inoue, Hirofumi Tenshin, Jumpei Teramachi, Ryohei Sumitani, Asuka Oda, Yusaku Maeda, Masahiro Oura, Kimiko Sogabe, Tomoko Maruhashi, Mamiko Takahashi, Shiro Fujii, Shingen Nakamura, Hirokazu Miki, Tomoyo Hara, Itsuro Endo, Kumiko Kagawa, Shuji Ozaki, Masahiro Hiasa, Takeshi Harada, Masahiro Abe","doi":"10.1111/cas.16401","DOIUrl":"10.1111/cas.16401","url":null,"abstract":"<p><p>Multiple myeloma (MM) cells and osteoclasts (OCs) activate with each other to cause drug resistance. Human Th1-like Vγ9Vδ2 (γδ) T cells, important effectors against tumors, can be expanded and activated ex vivo by the aminobisphosphonate zoledronic acid in combination with IL-2. We previously reported that the expanded γδ T cells effectively targeted and killed OCs as well as MM cells. Because the expanded γδ T cells expressed CD16 on their surface, we investigated the utilization of the expanded γδ T cells for antibody-dependent cellular cytotoxicity (ADCC). Although the expanded γδ T cells alone induced cell death in MM cell lines, the addition of the anti-SLAMF7 monoclonal antibody elotuzumab (ELO) further enhanced their cytotoxic activity only against SLAMF7-expressing MM cell lines and primary MM cells. Intriguingly, ELO was also able to enhance γδ T cell-induced cell death against OCs cultured alone, and against both MM cells and OCs in their coculture settings. SLAMF7 was found to be highly expressed in OCs differentiated in vitro from monocytes by receptor activator of nuclear factor-κ B ligand and M-CSF, although monocytes only marginally expressed SLAMF7. These results demonstrate that SLAMF7 is highly expressed in both MM cells and OCs, and that the ex vivo-expanded γδ T cells can exert ELO-mediated ADCC against SLAMF7-expressing MM cells and OCs besides their direct cytotoxic activity. Further study is warranted for the innovative utilization of γδ T cells.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}