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LINC02154 promotes cell cycle and mitochondrial function in oral squamous cell carcinoma. LINC02154 促进口腔鳞状细胞癌的细胞周期和线粒体功能
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2024-11-22 DOI: 10.1111/cas.16379
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

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.

长非编码RNA(lncRNA)在人类恶性肿瘤的发展过程中起着关键作用,但它们在口腔鳞状细胞癌(OSCC)中的参与情况仍不完全清楚。我们利用癌症基因组图谱(TCGA)数据集分析了原发性头颈部鳞状细胞癌(HNSCC)中7840个lncRNA的表达,发现LINC02154的上调与较差的预后有关。在 OSCC 细胞系中敲除 LINC02154 可诱导细胞周期停滞和细胞凋亡,并显著降低肿瘤在体外和体内的生长。值得注意的是,删除 LINC02154 会下调细胞周期相关基因的主调节因子 FOXM1。RNA pulldown和质谱分析发现了一系列可能与LINC02154相互作用的蛋白质,包括HNRNPK和LRPPRC。HNRNPK通过与FOXM1 mRNA的3'-UTR相互作用稳定了FOXM1的表达,这表明LINC02154和HNRNPK通过调节FOXM1的表达促进了细胞周期。此外,LINC02154 还通过抑制靶向 HNRPNK 的 microRNA 来正向调节 HNRNPK 的表达。此外,LINC02154 还通过与 LRPPRC 相互作用影响线粒体功能。删除 LINC02154 会抑制线粒体基因(包括 MTCO1 和 MTCO2)的表达,并抑制 OSCC 细胞的线粒体呼吸功能。这些结果表明,LINC02154通过调节OSCC中的细胞周期和氧化磷酸化来发挥其致癌作用,从而将LINC02154作为一个潜在的治疗靶点。
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引用次数: 0
Nelarabine-combined chemotherapy improves outcome of T-cell acute lymphoblastic leukemia but shows more severe neurotoxicity: JALSG T-ALL213-O. 奈拉滨联合化疗可改善T细胞急性淋巴细胞白血病的预后,但会产生更严重的神经毒性:JALSG T-ALL213-O。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2024-11-21 DOI: 10.1111/cas.16405
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

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).

我们研究了奈拉拉滨(NEL)联合化疗对新诊断的成人T细胞急性淋巴细胞白血病(T-ALL)患者的有效性和安全性。我们进行了一项名为T-ALL213-O的II期试验,25至64岁的成人T-ALL患者接受了基于我们之前的研究ALL202-O的方案治疗。从 ALL202-O 到 T-ALL213-O 的主要修改如下:(1) 对于诱导治疗(IND)1 后的非完全缓解(CR)患者,使用 NEL 联合化疗,而不是巩固治疗(C)1,作为 IND2;(2) 在第 29 天的 C3 和 C5 中插入 NEL 治疗。对 24 名患者进行了分析。10名患者因在C3前终止治疗而未接受NEL治疗。三年无事件生存率(EFS)为70%,90%置信区间的下限为52%,超过了25%的阈值;因此,研究治疗被认为是有效的。IND1、IND2和两者的CR率分别为75%、100%和88%。5年EFS和5年总生存率分别为66%和70%,中位随访时间分别为7.7年和7.8年。与ALL202-O中的T-ALL患者相比,加用NEL可提高CR率,但不能提高生存率。NEL用药后出现严重神经病变的频率很高。在接受NEL治疗的14名患者中,有7人(50%)出现了3级周围神经病变和/或步态障碍。神经毒性被认为比以前报告的更强。该剂量的NEL与强化多药化疗联合使用时,出现严重神经毒性的风险很高(JALSG T-ALL213-O, UMIN000010642)。
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引用次数: 0
Micropapillary structure: A natural tumor collective invasion model with enhanced stem-like properties. 微毛细血管结构:具有增强的干样特性的天然肿瘤集体侵袭模型。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2024-11-20 DOI: 10.1111/cas.16396
Sisi Li, Shuangshu Gao, Ling Qin, Caixia Ding, Jinghui Qu, Yifei Cui, Lixia Qiang, Shengjie Yin, Xiaoyu Zheng, Hongxue Meng

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.

癌症干细胞聚集成团,具有更强的干样特性和转移潜力。然而,癌症干细胞簇状结构的形成与获得更强的侵袭和转移能力的分子机制仍不清楚。微乳头状癌(MPC)是漂浮在基质中的一种小型、倒置、非纤维性血管簇亚群,存在于一系列实体恶性肿瘤中,以频繁的血管/淋巴管侵袭和淋巴结转移为特征。我们的研究结果表明,这些细胞簇表现出干细胞表型,支持了MPC可作为研究癌症干细胞簇侵袭和转移的实体肿瘤模型的前提。在这篇综述中,我们讨论了MPC研究和靶向治疗的最新进展,重点是分析其干细胞样特征、绘制其多组学特征图谱以及阐明MPC的血管和免疫微环境。我们利用现有的MPC类器官模型探索癌症干细胞集群靶向治疗和免疫治疗的潜在突破。
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引用次数: 0
Bacterial information in serum extracellular vesicles reflects the inflammation of adherent perinephric fat. 血清细胞外囊泡中的细菌信息反映了附着在肾周脂肪上的炎症。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2024-11-20 DOI: 10.1111/cas.16410
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

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。
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引用次数: 0
Leveraging genome-wide association studies to better understand the etiology of cancers. 利用全基因组关联研究更好地了解癌症病因。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2024-11-19 DOI: 10.1111/cas.16402
Kyuto Sonehara, Yukinori Okada

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.

全基因组关联研究(GWAS)对全基因组中数以千万计的遗传变异与相关表型之间的关联进行统计评估。全基因组关联研究有助于阐明癌症的多基因遗传性,在这种情况下,无数低婕妤度的遗传变异共同导致了相当大比例的遗传易感性。除了 GWAS 提供的强大基因型-表型关联外,将 GWAS 数据与功能基因组数据集或复杂的统计遗传方法相结合,还能获得更深入的见解。整合基因型和分子表型数据有助于通过分子定量性状位点图和转录组范围关联研究对 GWAS 关联信号进行功能表征。此外,汇总全基因组多基因信号(包括阈值下关联)可以估计不同表型的遗传相关性,并通过评估多基因风险评分帮助进行临床风险预测。在这篇综述中,我们首先总结了癌症全基因组分析的基本原理,介绍了全基因组分析下游分析方法的最新进展,并展示了它们在癌症全基因组分析中的应用。
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引用次数: 0
Rewired chromatin structure and epigenetic gene dysregulation during HTLV-1 infection to leukemogenesis. 从 HTLV-1 感染到白血病发生过程中的染色质结构改组和表观遗传基因失调。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2024-11-19 DOI: 10.1111/cas.16388
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.

人类T细胞白血病病毒1型(HTLV-1)广泛影响宿主基因,影响受感染的细胞群,诱发预后不良的疾病--成人T细胞白血病-淋巴瘤(ATL)。这项研究旨在提供受感染细胞群的全面表观基因组特征,并利用 RNA 测序(RNA-seq)和转座酶可检测染色质测序(ATAC-seq)评估了 HTLV-1 感染者外周血细胞的转录组和染色质结构。从多克隆阶段到ATL发病前,受感染细胞的基因表达模式发生了显著变化,同时显示出与形成肿瘤的ATL细胞的相似性。这些相似性是大规模开放染色质变化的结果,支持独立的表观基因组畸变的早期形成,这是后期克隆繁殖的潜在机制。这项研究还证明,HTLV-1 Tax 直接影响宿主染色质结构,从而形成基本的表观基因组特征。包括 RASGRP3-ERK 通路在内的几个 Tax 靶基因被确认,表明其对信号通路产生了影响。这种染色质结构特性的全基因组变异是 HTLV-1 感染的一个新特征,可能有助于致病机制。此外,它对更好地理解 HTLV-1 对宿主基因组的影响和确定新的治疗靶点也有重要意义。
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引用次数: 0
NETosis in pulmonary pleomorphic carcinoma. 肺胸膜癌中的 NETosis。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2024-11-18 DOI: 10.1111/cas.16332
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

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.

肺胸膜样癌(PC)是一种罕见的非小细胞肺癌(NSCLC),预后较差,以肿瘤坏死(TN)为特征。NETosis是中性粒细胞特异性细胞死亡的一种形式,其形态特征是坏死灶内中性粒细胞浸润和细胞碎片突出。本文共纳入了 76 例接受完全切除术的肺癌患者。通过对切除标本进行数字扫描,对肿瘤坏死情况进行评估。使用瓜氨酸组蛋白 H3(citH3)和髓过氧化物酶阳性区域对NETosis区域进行量化。我们研究了NETosis区域与预后结果之间的关联,并评估了NETosis区域与全身炎症之间的相关性。70例患者(92%)观察到肿瘤坏死。在所有病例中,TN 区域均伴有 citH3 阳性区域。NETosis面积大的患者(n = 54)的总生存期明显短于NETosis面积小的患者(n = 16)(p = 0.013)。此外,在多变量分析中,高NETosis面积是一个独立的不良预后因素。高NETosis面积患者的全身炎症指标,包括C反应蛋白(CRP)、CRP-白蛋白比值和中性粒细胞-淋巴细胞比值均显著高于低NETosis面积患者。此外,这些炎症标志物的水平在手术后明显降低。这项研究表明,在手术切除的肺癌患者中,NETosis面积大的患者全身炎症程度更高,预后更差。
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引用次数: 0
Current status and future direction of cancer research using artificial intelligence for clinical application. 将人工智能应用于临床的癌症研究现状和未来方向。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2024-11-18 DOI: 10.1111/cas.16395
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

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.

近年来,人们对人工智能(AI)技术的期望大大提高,这主要归功于深度学习的出现。目前,人工智能技术正被用于各种用途,并给社会带来了变革。特别是以 ChatGPT 为代表的生成式人工智能技术的快速发展,扩大了人工智能的社会影响。医学领域也不例外,在基础研究和应用研究中引入了各种人工智能技术。此外,配备人工智能的软件作为医疗设备(AI-SaMD)也正在获得监管机构的批准。随着大数据时代的到来,利用人工智能的数据驱动型研究也在积极推进。然而,虽然人工智能技术具有巨大的潜力,但它也带来了许多挑战,需要仔细考虑。在这篇综述中,我们将介绍基于人工智能的癌症研究现状,尤其是从临床应用的角度,并讨论相关挑战和未来方向,旨在帮助促进有效利用人工智能技术的癌症研究。
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引用次数: 0
Diagnosis and typing of leukemia using a single peripheral blood cell through deep learning. 通过深度学习,利用单个外周血细胞对白血病进行诊断和分型。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2024-11-18 DOI: 10.1111/cas.16374
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.

白血病具有高度异质性,这意味着不同类型的白血病需要不同的治疗方法,预后也不尽相同。目前的临床诊断和分型测试既复杂又耗时。尤其是,所有这些检测都依赖于骨髓抽吸,而骨髓抽吸是侵入性的,会导致患者依从性差,加剧治疗延误。外周血细胞(PBC)的形态学分析仍主要用于区分良性和恶性血液病,但仅靠人类专家直接观察外周血涂片来诊断和分型这些疾病仍是一项挑战。在本研究中,我们应用了基于分割的增强残差网络,该网络使用拼图补丁进行渐进式多粒度训练。它在一个自建的标注数据集上进行训练,该数据集包含来自 237 名患者的 21 208 张图像,其中包括五种良性白细胞和八种白血病细胞。该网络不仅能区分良性和恶性细胞,还能利用单个外周血细胞对白血病进行分型。该网络能有效区分急性早幼粒细胞白血病(APL)和其他类型的急性髓性白血病(非 APL),APL 的精确率为 89.34%,召回率为 97.37%,F1 得分为 93.18%。相反,对于非 APL 病例,该模型的精确率为 92.86%,但召回率为 74.63%,F1 得分为 82.75%。此外,该模型还能区分带有 Ph 染色体的急性淋巴细胞白血病(ALL)和不带有 Ph 染色体的急性淋巴细胞白血病(ALL)。这种方法可以提高患者的依从性,并能更快、更准确地对白血病进行分型,以便早期诊断和治疗,从而提高生存率。
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引用次数: 0
Elotuzumab-mediated ADCC with Th1-like Vγ9Vδ2 T cells to disrupt myeloma-osteoclast interaction. 艾洛妥珠单抗介导的Th1样Vγ9Vδ2 T细胞ADCC可破坏骨髓瘤与破骨细胞之间的相互作用。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2024-11-18 DOI: 10.1111/cas.16401
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

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。
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Cancer Science
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