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Explainable artificial intelligence in breast cancer detection and risk prediction: A systematic scoping review 可解释人工智能在乳腺癌检测和风险预测中的应用:系统性范围审查
Pub Date : 2024-07-03 DOI: 10.1002/cai2.136
Amirehsan Ghasemi, Soheil Hashtarkhani, David L. Schwartz, Arash Shaban-Nejad

With the advances in artificial intelligence (AI), data-driven algorithms are becoming increasingly popular in the medical domain. However, due to the nonlinear and complex behavior of many of these algorithms, decision-making by such algorithms is not trustworthy for clinicians and is considered a black-box process. Hence, the scientific community has introduced explainable artificial intelligence (XAI) to remedy the problem. This systematic scoping review investigates the application of XAI in breast cancer detection and risk prediction. We conducted a comprehensive search on Scopus, IEEE Explore, PubMed, and Google Scholar (first 50 citations) using a systematic search strategy. The search spanned from January 2017 to July 2023, focusing on peer-reviewed studies implementing XAI methods in breast cancer datasets. Thirty studies met our inclusion criteria and were included in the analysis. The results revealed that SHapley Additive exPlanations (SHAP) is the top model-agnostic XAI technique in breast cancer research in terms of usage, explaining the model prediction results, diagnosis and classification of biomarkers, and prognosis and survival analysis. Additionally, the SHAP model primarily explained tree-based ensemble machine learning models. The most common reason is that SHAP is model agnostic, which makes it both popular and useful for explaining any model prediction. Additionally, it is relatively easy to implement effectively and completely suits performant models, such as tree-based models. Explainable AI improves the transparency, interpretability, fairness, and trustworthiness of AI-enabled health systems and medical devices and, ultimately, the quality of care and outcomes.

随着人工智能(AI)的发展,数据驱动算法在医疗领域越来越受欢迎。然而,由于许多此类算法的非线性和复杂行为,临床医生对此类算法的决策并不信任,认为这是一个黑箱过程。因此,科学界引入了可解释人工智能(XAI)来解决这一问题。本系统性范围综述调查了 XAI 在乳腺癌检测和风险预测中的应用。我们采用系统性检索策略,在 Scopus、IEEE Explore、PubMed 和 Google Scholar(前 50 篇引文)上进行了全面检索。搜索时间跨度为 2017 年 1 月至 2023 年 7 月,重点关注在乳腺癌数据集中采用 XAI 方法的同行评审研究。有 30 项研究符合我们的纳入标准并被纳入分析。结果显示,在乳腺癌研究中,SHapley Additive exPlanations(SHAP)在使用、解释模型预测结果、生物标记物的诊断和分类以及预后和生存分析方面是最重要的模型诊断 XAI 技术。此外,SHAP 模型主要解释了基于树的集合机器学习模型。最常见的原因是,SHAP 与模型无关,这使得它在解释任何模型预测结果时既受欢迎又有用。此外,它相对容易有效实现,完全适合性能良好的模型,如基于树的模型。可解释的人工智能提高了人工智能医疗系统和医疗设备的透明度、可解释性、公平性和可信度,并最终提高了医疗质量和结果。
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引用次数: 0
Radiomics models to predict bone marrow metastasis of neuroblastoma using CT 利用CT预测神经母细胞瘤骨髓转移的放射组学模型
Pub Date : 2024-06-28 DOI: 10.1002/cai2.135
Xiong Chen, Qinchang Chen, Yuanfang Liu, Ya Qiu, Lin Lv, Zhengtao Zhang, Xuntao Yin, Fangpeng Shu

Background

Bone marrow is the leading site for metastasis from neuroblastoma and affects the prognosis of patients with neuroblastoma. However, the accurate diagnosis of bone marrow metastasis is limited by the high spatial and temporal heterogeneity of neuroblastoma. Radiomics analysis has been applied in various cancers to build accurate diagnostic models but has not yet been applied to bone marrow metastasis of neuroblastoma.

Methods

We retrospectively collected information from 187 patients pathologically diagnosed with neuroblastoma and divided them into training and validation sets in a ratio of 7:3. A total of 2632 radiomics features were retrieved from venous and arterial phases of contrast-enhanced computed tomography (CT), and nine machine learning approaches were used to build radiomics models, including multilayer perceptron (MLP), extreme gradient boosting, and random forest. We also constructed radiomics-clinical models that combined radiomics features with clinical predictors such as age, gender, ascites, and lymph gland metastasis. The performance of the models was evaluated with receiver operating characteristics (ROC) curves, calibration curves, and risk decile plots.

Results

The MLP radiomics model yielded an area under the ROC curve (AUC) of 0.97 (95% confidence interval [CI]: 0.95–0.99) on the training set and 0.90 (95% CI: 0.82–0.95) on the validation set. The radiomics-clinical model using an MLP yielded an AUC of 0.93 (95% CI: 0.89–0.96) on the training set and 0.91 (95% CI: 0.85–0.97) on the validation set.

Conclusions

MLP-based radiomics and radiomics-clinical models can precisely predict bone marrow metastasis in patients with neuroblastoma.

背景:骨髓是神经母细胞瘤转移的主要部位,影响神经母细胞瘤患者的预后。然而,由于神经母细胞瘤在空间和时间上的高度异质性,骨髓转移的准确诊断受到了限制。放射组学分析已应用于多种癌症,以建立准确的诊断模型,但尚未应用于神经母细胞瘤的骨髓转移:我们回顾性地收集了 187 例经病理诊断为神经母细胞瘤患者的信息,并按 7:3 的比例将其分为训练集和验证集。我们从造影剂增强计算机断层扫描(CT)的静脉期和动脉期提取了共 2632 个放射组学特征,并使用九种机器学习方法建立放射组学模型,包括多层感知器(MLP)、极梯度提升和随机森林。我们还构建了放射组学-临床模型,将放射组学特征与年龄、性别、腹水和淋巴腺转移等临床预测因素相结合。我们用接收者操作特征曲线(ROC)、校准曲线和风险十等分图来评估模型的性能:MLP 放射组学模型在训练集上的 ROC 曲线下面积(AUC)为 0.97(95% 置信区间 [CI]:0.95-0.99),在验证集上的 ROC 曲线下面积(AUC)为 0.90(95% 置信区间 [CI]:0.82-0.95)。使用 MLP 的放射组学-临床模型在训练集上的 AUC 为 0.93(95% CI:0.89-0.96),在验证集上的 AUC 为 0.91(95% CI:0.85-0.97):基于MLP的放射组学和放射组学-临床模型可以准确预测神经母细胞瘤患者的骨髓转移。
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引用次数: 0
High-fat-diet-induced obesity promotes simultaneous progression of lung cancer and atherosclerosis in apolipoprotein E-knockout mice 高脂饮食诱发的肥胖会同时促进载脂蛋白 E 基因敲除小鼠肺癌和动脉粥样硬化的发展
Pub Date : 2024-06-05 DOI: 10.1002/cai2.127
Yihao Wang, Kaixin Yan, Han Duan, Ning Tao, Shaoning Zhu, Yuning Zhang, Yonggang You, Zhen Zhang, Hua Wang, Shunying Hu

Background

Clinical studies have shown that atherosclerotic cardiovascular disease and cancer often co-exist in the same individual. The present study aimed to investigate the role of high-fat-diet (HFD)-induced obesity in the coexistence of the two diseases and the underlying mechanism in apolipoprotein E-knockout (ApoE−/−) mice.

Methods

Male ApoE−/− mice were fed with a HFD or a normal diet (ND) for 15 weeks. On the first day of Week 13, the mice were inoculated subcutaneously in the right axilla with Lewis lung cancer cells. At Weeks 12 and 15, serum lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and vascular endothelial growth factor levels were measured by enzyme-linked immunosorbent assay, and blood monocytes and macrophages were measured by fluorescence-activated cell sorting. At Week 15, the volume and weight of the local subcutaneous lung cancer and metastatic lung cancer and the amount of aortic atherosclerosis were measured.

Results

At Week 15, compared with mice in the ND group, those in the HFD group had a larger volume of local subcutaneous cancer (p = 0.0004), heavier tumors (p = 0.0235), more metastatic cancer in the lungs (p < 0.0001), a larger area of lung involved in metastatic cancer (p = 0.0031), and larger areas of atherosclerosis in the aorta (p < 0.0001). At Week 12, serum LOX-1, serum vascular endothelial growth factor, and proportions of blood monocytes and macrophages were significantly higher in the HFD group than those in the ND group (p = 0.0002, p = 0.0029, p = 0.0480, and p = 0.0106, respectively); this trend persisted until Week 15 (p = 0.0014, p = 0.0012, p = 0.0001, and p = 0.0204).

Conclusions

In this study, HFD-induced obesity could simultaneously promote progression of lung cancer and atherosclerosis in the same mouse. HFD-induced upregulation of LOX-1 may play an important role in the simultaneous progression of these two conditions via the inflammatory response and VEGF.

背景 临床研究表明,动脉粥样硬化性心血管疾病和癌症往往在同一个人身上同时存在。本研究旨在通过载脂蛋白 E 基因敲除(ApoE-/-)小鼠,探讨高脂饮食(HFD)诱导肥胖在两种疾病并存中的作用及其内在机制。 方法 雄性载脂蛋白E-/-小鼠以高密度脂蛋白饮食(HFD)或正常饮食(ND)喂养15周。第 13 周的第一天,在小鼠右腋窝皮下接种 Lewis 肺癌细胞。第12周和第15周,用酶联免疫吸附试验测定血清凝集素样氧化低密度脂蛋白受体-1(LOX-1)和血管内皮生长因子水平,用荧光激活细胞分选法测定血液中的单核细胞和巨噬细胞。第 15 周时,测量局部皮下肺癌和转移性肺癌的体积和重量以及主动脉粥样硬化的程度。 结果 第15周时,与ND组小鼠相比,HFD组小鼠的局部皮下癌体积更大(p = 0.0004)、肿瘤更重(p = 0.0235)、肺部转移癌更多(p < 0.0001)、转移癌涉及的肺部面积更大(p = 0.0031)、主动脉粥样硬化面积更大(p < 0.0001)。第 12 周时,HFD 组的血清 LOX-1、血清血管内皮生长因子以及血液中单核细胞和巨噬细胞的比例显著高于 ND 组(分别为 p = 0.0002、p = 0.0029、p = 0.0480 和 p = 0.0106);这一趋势一直持续到第 15 周(p = 0.0014、p = 0.0012、p = 0.0001 和 p = 0.0204)。 结论 在本研究中,HFD 诱导的肥胖可同时促进肺癌和动脉粥样硬化在同一只小鼠中的发展。高频分解膳食诱导的 LOX-1 上调可能通过炎症反应和血管内皮生长因子在这两种疾病的同时进展中发挥了重要作用。
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引用次数: 0
Efficacy and safety of first-line regimens for advanced HER2-positive breast cancer: A Bayesian network meta-analysis 晚期 HER2 阳性乳腺癌一线治疗方案的疗效和安全性:贝叶斯网络荟萃分析
Pub Date : 2024-05-22 DOI: 10.1002/cai2.126
Lixi Li, Yun Wu, Bo Lan, Fei Ma

Background

The current standard of care for advanced human epidermal growth factor receptor 2 (HER2)-positive breast cancer is pertuzumab plus trastuzumab and docetaxel as first-line therapy. However, with the development of newer treatment regimens, there is a lack of evidence regarding which is the optimal treatment strategy. The aim of this network meta-analysis was to evaluate the efficacy and safety of first-line regimens for advanced HER2-positive breast cancer by indirect comparisons.

Methods

A systematic review and Bayesian network meta-analysis were conducted. The PubMed, EMBASE, and Cochrane Library databases were searched for relevant articles published through to December 2023. The hazard ratio (HR) and 95% credible interval (CrI) were used to compare progression-free survival (PFS) between treatments, and the odds ratio and 95% CrI were used to compare the objective response rate (ORR) and safety.

Results

Twenty randomized clinical trials that included 15 regimens and 7094 patients were analyzed. Compared with the traditional trastuzumab and docetaxel regimen, PFS was longer on the pyrotinib and trastuzumab plus docetaxel regimen (HR: 0.41, 95% CrI: 0.22–0.75) and the pertuzumab and trastuzumab plus docetaxel regimen (HR: 0.65, 95% CrI: 0.43–0.98). Consistent with the results for PFS, the ORR was better on the pyrotinib and trastuzumab plus docetaxel regimen and the pertuzumab and trastuzumab plus docetaxel regimen than on the traditional trastuzumab and docetaxel regimen. The surface under the cumulative ranking curve indicated that the pyrotinib and trastuzumab plus docetaxel regimen was most likely to rank first in achieving the best PFS and ORR. Comparable results were found for grade ≥3 AE rates of ≥10%.

Conclusions

Our results suggest that the pyrotinib and trastuzumab plus docetaxel regimen is most likely to be the optimal first-line therapy for patients with HER2-positive breast cancer.

背景晚期人表皮生长因子受体 2 (HER2) 阳性乳腺癌目前的一线治疗标准是百妥珠单抗加曲妥珠单抗和多西他赛。然而,随着新治疗方案的不断开发,关于哪种治疗方法是最佳治疗策略的证据仍然缺乏。本网络荟萃分析旨在通过间接比较评估晚期HER2阳性乳腺癌一线治疗方案的有效性和安全性。 方法 进行了系统综述和贝叶斯网络荟萃分析。在 PubMed、EMBASE 和 Cochrane Library 数据库中检索了截至 2023 年 12 月发表的相关文章。采用危险比(HR)和 95% 可信区间(CrI)来比较不同疗法的无进展生存期(PFS),采用几率比和 95% 可信区间(CrI)来比较客观反应率(ORR)和安全性。 结果 分析了20项随机临床试验,包括15种方案和7094名患者。与传统的曲妥珠单抗和多西他赛方案相比,吡罗替尼和曲妥珠单抗加多西他赛方案(HR:0.41,95% CrI:0.22-0.75)以及百妥珠单抗和曲妥珠单抗加多西他赛方案(HR:0.65,95% CrI:0.43-0.98)的PFS更长。与PFS结果一致,吡罗替尼和曲妥珠单抗加多西他赛方案以及pertuzumab和曲妥珠单抗加多西他赛方案的ORR优于传统的曲妥珠单抗和多西他赛方案。累积排名曲线下表面显示,在获得最佳PFS和ORR方面,吡罗替尼和曲妥珠单抗加多西他赛方案最有可能排名第一。≥10%的≥3级AE发生率也有类似结果。 结论 我们的研究结果表明,对于HER2阳性乳腺癌患者,吡罗替尼和曲妥珠单抗加多西他赛方案最有可能成为最佳一线疗法。
{"title":"Efficacy and safety of first-line regimens for advanced HER2-positive breast cancer: A Bayesian network meta-analysis","authors":"Lixi Li,&nbsp;Yun Wu,&nbsp;Bo Lan,&nbsp;Fei Ma","doi":"10.1002/cai2.126","DOIUrl":"https://doi.org/10.1002/cai2.126","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The current standard of care for advanced human epidermal growth factor receptor 2 (HER2)-positive breast cancer is pertuzumab plus trastuzumab and docetaxel as first-line therapy. However, with the development of newer treatment regimens, there is a lack of evidence regarding which is the optimal treatment strategy. The aim of this network meta-analysis was to evaluate the efficacy and safety of first-line regimens for advanced HER2-positive breast cancer by indirect comparisons.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A systematic review and Bayesian network meta-analysis were conducted. The PubMed, EMBASE, and Cochrane Library databases were searched for relevant articles published through to December 2023. The hazard ratio (HR) and 95% credible interval (CrI) were used to compare progression-free survival (PFS) between treatments, and the odds ratio and 95% CrI were used to compare the objective response rate (ORR) and safety.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Twenty randomized clinical trials that included 15 regimens and 7094 patients were analyzed. Compared with the traditional trastuzumab and docetaxel regimen, PFS was longer on the pyrotinib and trastuzumab plus docetaxel regimen (HR: 0.41, 95% CrI: 0.22–0.75) and the pertuzumab and trastuzumab plus docetaxel regimen (HR: 0.65, 95% CrI: 0.43–0.98). Consistent with the results for PFS, the ORR was better on the pyrotinib and trastuzumab plus docetaxel regimen and the pertuzumab and trastuzumab plus docetaxel regimen than on the traditional trastuzumab and docetaxel regimen. The surface under the cumulative ranking curve indicated that the pyrotinib and trastuzumab plus docetaxel regimen was most likely to rank first in achieving the best PFS and ORR. Comparable results were found for grade ≥3 AE rates of ≥10%.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our results suggest that the pyrotinib and trastuzumab plus docetaxel regimen is most likely to be the optimal first-line therapy for patients with HER2-positive breast cancer.</p>\u0000 </section>\u0000 </div>","PeriodicalId":100212,"journal":{"name":"Cancer Innovation","volume":"3 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cai2.126","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141078964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Identification of NR3C2 as a functional diagnostic and prognostic biomarker and potential therapeutic target in non-small cell lung cancer 将 NR3C2 鉴定为非小细胞肺癌的功能性诊断和预后生物标记物及潜在治疗靶点
Pub Date : 2024-05-21 DOI: 10.1002/cai2.122
Yuan-yuan Sun, Hai-cheng Gao, Peng Guo, Na Sun, Chan Peng, Zhi-hua Cheng, Jing Gu, Jin-yi Liu, Fei Han

Background

Non-small cell lung cancer (NSCLC), including the lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) subtypes, is a malignant tumor type with a poor 5-year survival rate. The identification of new powerful diagnostic biomarkers, prognostic biomarkers, and potential therapeutic targets in NSCLC is urgently required.

Methods

The UCSC Xena, UALCAN, and GEO databases were used to screen and analyze differentially expressed genes, regulatory modes, and genetic/epigenetic alterations in NSCLC. The UCSC Xena database, GEO database, tissue microarray, and immunohistochemistry staining analyses were used to evaluate the diagnostic and prognostic values. Gain-of-function assays were performed to examine the roles. The ESTIMATE, TIMER, Linked Omics, STRING, and DAVID algorithms were used to analyze potential molecular mechanisms.

Results

NR3C2 was identified as a potentially important molecule in NSCLC. NR3C2 is expressed at low levels in NSCLC, LUAD, and LUSC tissues, which is significantly related to the clinical indexes of these patients. Receiver operating characteristic curve analysis suggests that the altered NR3C2 expression patterns have diagnostic value in NSCLC, LUAD, and especially LUSC patients. Decreased NR3C2 expression levels can help predict poor prognosis in NSCLC and LUAD patients but not in LUSC patients. These results have been confirmed both with database analysis and real-world clinical samples on a tissue microarray. Copy number variation contributes to low NR3C2 expression levels in NSCLC and LUAD, while promoter DNA methylation is involved in its downregulation in LUSC. Two NR3C2 promoter methylation sites have high sensitivity and specificity for LUSC diagnosis with clinical application potential. NR3C2 may be a key participant in NSCLC development and progression and is closely associated with the tumor microenvironment and immune cell infiltration. NR3C2 co-expressed genes are involved in many cancer-related signaling pathways, further supporting a potentially significant role of NR3C2 in NSCLC.

Conclusions

NR3C2 is a novel potential diagnostic and prognostic biomarker and therapeutic target in NSCLC.

背景 非小细胞肺癌(NSCLC),包括肺鳞状细胞癌(LUSC)和肺腺癌(LUAD)亚型,是一种 5 年生存率很低的恶性肿瘤类型。目前迫切需要鉴定新的强效诊断生物标志物、预后生物标志物和 NSCLC 的潜在治疗靶点。 方法 利用 UCSC Xena、UALCAN 和 GEO 数据库筛选和分析 NSCLC 中的差异表达基因、调控模式和遗传/表观遗传学改变。UCSC Xena数据库、GEO数据库、组织芯片和免疫组化染色分析用于评估诊断和预后价值。此外,还进行了功能增益分析以研究其作用。使用ESTIMATE、TIMER、Linked Omics、STRING和DAVID算法分析潜在的分子机制。 结果 NR3C2 被确定为 NSCLC 中潜在的重要分子。NR3C2在NSCLC、LUAD和LUSC组织中低水平表达,与这些患者的临床指标显著相关。接收者操作特征曲线分析表明,NR3C2表达模式的改变对NSCLC、LUAD,尤其是LUSC患者具有诊断价值。NR3C2 表达水平的降低有助于预测 NSCLC 和 LUAD 患者的不良预后,但不能预测 LUSC 患者的不良预后。这些结果已通过数据库分析和组织芯片上的实际临床样本得到证实。拷贝数变异导致了NSCLC和LUAD中NR3C2的低表达水平,而启动子DNA甲基化参与了LUSC中NR3C2的下调。两个NR3C2启动子甲基化位点对LUSC诊断具有高敏感性和特异性,具有临床应用潜力。NR3C2可能是NSCLC发生和发展的关键参与者,与肿瘤微环境和免疫细胞浸润密切相关。NR3C2 共表达基因参与了许多与癌症相关的信号通路,进一步证实了 NR3C2 在 NSCLC 中的潜在重要作用。 结论 NR3C2 是一种新的潜在的 NSCLC 诊断和预后生物标记物及治疗靶点。
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引用次数: 0
Integrative analyses identified gap junction beta-2 as a prognostic biomarker and therapeutic target for breast cancer 综合分析发现间隙连接β-2是乳腺癌的预后生物标志物和治疗靶点
Pub Date : 2024-05-19 DOI: 10.1002/cai2.128
Di Zhang, Lixi Li, Fei Ma

Background

Increasing evidence has shown that connexins are involved in the regulation of tumor development, immune escape, and drug resistance. This study investigated the gene expression patterns, prognostic values, and potential mechanisms of connexins in breast cancer.

Methods

We conducted a comprehensive analysis of connexins using public gene and protein expression databases and clinical samples from our institution. Connexin mRNA expressions in breast cancer and matched normal tissues were compared, and multiomics studies were performed.

Results

Gap junction beta-2 mRNA was overexpressed in breast cancers of different pathological types and molecular subtypes, and its high expression was associated with poor prognosis. The tumor membrane of the gap junction beta-2 mutated group was positive, and the corresponding protein was expressed. Somatic mutation and copy number variation of gap junction beta-2 are rare in breast cancer. The gap junction beta-2 transcription level in the p110α subunit of the phosphoinositide 3-kinase mutant subgroup was higher than that in the wild-type subgroup. Gap junction beta-2 was associated with the phosphoinositide 3-kinase-Akt signaling pathway, extracellular matrix–receptor interaction, focal adhesion, and proteoglycans in cancer. Furthermore, gap junction beta-2 overexpression may be associated with phosphoinositide 3-kinase and histone deacetylase inhibitor resistance, and its expression level correlated with infiltrating CD8+ T cells, macrophages, neutrophils, and dendritic cells.

Conclusions

Gap junction beta-2 may be a promising therapeutic target for targeted therapy and immunotherapy and may be used to predict breast cancer prognosis.

背景 越来越多的证据表明,连接蛋白参与了肿瘤发生、免疫逃逸和耐药性的调控。本研究调查了乳腺癌中连接蛋白的基因表达模式、预后价值和潜在机制。 方法 我们利用公共基因和蛋白质表达数据库以及本机构的临床样本对连接蛋白进行了全面分析。比较了乳腺癌和匹配的正常组织中连接蛋白 mRNA 的表达,并进行了多组学研究。 结果 间隙连接β-2 mRNA在不同病理类型和分子亚型的乳腺癌中均有过表达,且其高表达与预后不良有关。间隙连接β-2突变组的肿瘤膜呈阳性,并表达相应的蛋白。间隙连接β-2的体细胞突变和拷贝数变异在乳腺癌中很少见。磷酸肌酸 3-激酶 p110α 亚基突变亚组的间隙连接β-2转录水平高于野生型亚组。在癌症中,间隙连接β-2与磷酸肌醇3-激酶-Akt信号通路、细胞外基质-受体相互作用、病灶粘附和蛋白聚糖有关。此外,间隙连接β-2的过表达可能与磷酸肌酸3-激酶和组蛋白去乙酰化酶抑制剂的抗性有关,其表达水平与浸润的CD8+ T细胞、巨噬细胞、中性粒细胞和树突状细胞相关。 结论 Gap junction beta-2 可能是靶向治疗和免疫治疗的一个有前途的治疗靶点,并可用于预测乳腺癌的预后。
{"title":"Integrative analyses identified gap junction beta-2 as a prognostic biomarker and therapeutic target for breast cancer","authors":"Di Zhang,&nbsp;Lixi Li,&nbsp;Fei Ma","doi":"10.1002/cai2.128","DOIUrl":"https://doi.org/10.1002/cai2.128","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Increasing evidence has shown that connexins are involved in the regulation of tumor development, immune escape, and drug resistance. This study investigated the gene expression patterns, prognostic values, and potential mechanisms of connexins in breast cancer.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We conducted a comprehensive analysis of connexins using public gene and protein expression databases and clinical samples from our institution. Connexin mRNA expressions in breast cancer and matched normal tissues were compared, and multiomics studies were performed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Gap junction beta-2 mRNA was overexpressed in breast cancers of different pathological types and molecular subtypes, and its high expression was associated with poor prognosis. The tumor membrane of the gap junction beta-2 mutated group was positive, and the corresponding protein was expressed. Somatic mutation and copy number variation of gap junction beta-2 are rare in breast cancer. The gap junction beta-2 transcription level in the p110α subunit of the phosphoinositide 3-kinase mutant subgroup was higher than that in the wild-type subgroup. Gap junction beta-2 was associated with the phosphoinositide 3-kinase-Akt signaling pathway, extracellular matrix–receptor interaction, focal adhesion, and proteoglycans in cancer. Furthermore, gap junction beta-2 overexpression may be associated with phosphoinositide 3-kinase and histone deacetylase inhibitor resistance, and its expression level correlated with infiltrating CD8+ T cells, macrophages, neutrophils, and dendritic cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Gap junction beta-2 may be a promising therapeutic target for targeted therapy and immunotherapy and may be used to predict breast cancer prognosis.</p>\u0000 </section>\u0000 </div>","PeriodicalId":100212,"journal":{"name":"Cancer Innovation","volume":"3 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cai2.128","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141069113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A lactate-responsive gene signature predicts the prognosis and immunotherapeutic response of patients with triple-negative breast cancer 乳酸反应基因特征可预测三阴性乳腺癌患者的预后和免疫治疗反应
Pub Date : 2024-05-17 DOI: 10.1002/cai2.124
Kaixiang Feng, Youcheng Shao, Jun Li, Xiaoqing Guan, Qin Liu, Meishun Hu, Mengfei Chu, Hui Li, Fangfang Chen, Zongbi Yi, Jingwei Zhang

Background

Increased glycolytic activity and lactate production are characteristic features of triple-negative breast cancer (TNBC). The aim of this study was to determine whether a subset of lactate-responsive genes (LRGs) could be used to classify TNBC subtypes and predict patient outcomes.

Methods

Lactate levels were initially measured in different breast cancer (BC) cell types. Subsequently, MDA-MB-231 cells treated with 2-Deoxy-d-glucose or l-lactate were subjected to RNA sequencing (RNA-seq). The gene set variation analysis algorithm was utilized to calculate the lactate-responsive score, conduct a differential analysis, and establish an association with the extent of immune infiltration. Consensus clustering was then employed to classify TNBC patients. Tumor immune dysfunction and exclusion, cibersort, single-sample gene set enrichment analysis, and EPIC, were used to compare the tumor-infiltrating immune cells between TNBC subtypes and predict the response to immunotherapy. Furthermore, a prognostic model was developed by combining 98 machine learning algorithms, to assess the predictive significance of the LRG signature. The predictive value of immune infiltration and the immunotherapy response was also assessed. Finally, the association between lactate and various anticancer drugs was examined based on expression profile similarity principles.

Results

We found that the lactate levels of TNBC cells were significantly higher than those of other BC cell lines. Through RNA-seq, we identified 14 differentially expressed LRGs in TNBC cells under varying lactate levels. Notably, this LRG signature was associated with interleukin-17 signaling pathway dysregulation, suggesting a link between lactate metabolism and immune impairment. Furthermore, the LRG signature was used to categorize TNBC into two distinct subtypes, whereby Subtype A was characterized by immunosuppression, whereas Subtype B was characterized by immune activation.

Conclusion

We identified an LRG signature in TNBC, which could be used to predict the prognosis of patients with TNBC and gauge their response to immunotherapy. Our findings may help guide the precision treatment of patients with TNBC.

背景 糖酵解活性和乳酸生成增加是三阴性乳腺癌(TNBC)的特征。本研究旨在确定乳酸反应基因(LRGs)子集是否可用于 TNBC 亚型的分类和患者预后的预测。 方法 首先测量不同乳腺癌(BC)细胞类型的乳酸水平。随后,对用 2-Deoxy-d-glucose 或 l-Lactate 处理的 MDA-MB-231 细胞进行 RNA 测序(RNA-seq)。利用基因组变异分析算法计算乳酸反应得分,进行差异分析,并建立与免疫浸润程度的关联。然后采用共识聚类对 TNBC 患者进行分类。利用肿瘤免疫功能障碍和排除、cibersort、单样本基因组富集分析和EPIC等方法比较TNBC亚型之间的肿瘤浸润免疫细胞,并预测对免疫疗法的反应。此外,还结合98种机器学习算法建立了预后模型,以评估LRG特征的预测意义。同时还评估了免疫浸润和免疫治疗反应的预测价值。最后,根据表达谱相似性原则研究了乳酸盐与各种抗癌药物之间的关联。 结果 我们发现 TNBC 细胞的乳酸水平明显高于其他 BC 细胞系。通过 RNA-seq,我们在不同乳酸水平的 TNBC 细胞中发现了 14 个差异表达的 LRG。值得注意的是,这一LRG特征与白细胞介素-17信号通路失调有关,表明乳酸代谢与免疫损伤之间存在联系。此外,LRG特征还被用于将TNBC分为两种不同的亚型,其中A亚型的特点是免疫抑制,而B亚型的特点是免疫激活。 结论 我们在 TNBC 中发现了一种 LRG 特征,它可用于预测 TNBC 患者的预后并衡量他们对免疫疗法的反应。我们的发现可能有助于指导 TNBC 患者的精准治疗。
{"title":"A lactate-responsive gene signature predicts the prognosis and immunotherapeutic response of patients with triple-negative breast cancer","authors":"Kaixiang Feng,&nbsp;Youcheng Shao,&nbsp;Jun Li,&nbsp;Xiaoqing Guan,&nbsp;Qin Liu,&nbsp;Meishun Hu,&nbsp;Mengfei Chu,&nbsp;Hui Li,&nbsp;Fangfang Chen,&nbsp;Zongbi Yi,&nbsp;Jingwei Zhang","doi":"10.1002/cai2.124","DOIUrl":"https://doi.org/10.1002/cai2.124","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Increased glycolytic activity and lactate production are characteristic features of triple-negative breast cancer (TNBC). The aim of this study was to determine whether a subset of lactate-responsive genes (LRGs) could be used to classify TNBC subtypes and predict patient outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Lactate levels were initially measured in different breast cancer (BC) cell types. Subsequently, MDA-MB-231 cells treated with 2-Deoxy-<span>d</span>-glucose or <span>l</span>-lactate were subjected to RNA sequencing (RNA-seq). The gene set variation analysis algorithm was utilized to calculate the lactate-responsive score, conduct a differential analysis, and establish an association with the extent of immune infiltration. Consensus clustering was then employed to classify TNBC patients. Tumor immune dysfunction and exclusion, cibersort, single-sample gene set enrichment analysis, and EPIC, were used to compare the tumor-infiltrating immune cells between TNBC subtypes and predict the response to immunotherapy. Furthermore, a prognostic model was developed by combining 98 machine learning algorithms, to assess the predictive significance of the LRG signature. The predictive value of immune infiltration and the immunotherapy response was also assessed. Finally, the association between lactate and various anticancer drugs was examined based on expression profile similarity principles.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We found that the lactate levels of TNBC cells were significantly higher than those of other BC cell lines. Through RNA-seq, we identified 14 differentially expressed LRGs in TNBC cells under varying lactate levels. Notably, this LRG signature was associated with interleukin-17 signaling pathway dysregulation, suggesting a link between lactate metabolism and immune impairment. Furthermore, the LRG signature was used to categorize TNBC into two distinct subtypes, whereby Subtype A was characterized by immunosuppression, whereas Subtype B was characterized by immune activation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>We identified an LRG signature in TNBC, which could be used to predict the prognosis of patients with TNBC and gauge their response to immunotherapy. Our findings may help guide the precision treatment of patients with TNBC.</p>\u0000 </section>\u0000 </div>","PeriodicalId":100212,"journal":{"name":"Cancer Innovation","volume":"3 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cai2.124","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141069180","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Identification of collagen subtypes of gastric cancer for distinguishing patient prognosis and therapeutic response 识别胃癌胶原蛋白亚型以区分患者预后和治疗反应
Pub Date : 2024-05-16 DOI: 10.1002/cai2.125
Di Wang, Jing Zhang, Jianchao Wang, Zhonglin Cai, Shanfeng Jin, Gang Chen

Background

Gastric cancer is a highly heterogeneous disease, presenting a major obstacle to personalized treatment. Effective markers of the immune checkpoint blockade response are needed for precise patient classification. We, therefore, divided patients with gastric cancer according to collagen gene expression to indicate their prognosis and treatment response.

Methods

We collected data for 1250 patients with gastric cancer from four cohorts. For the TCGA-STAD cohort, we used consensus clustering to stratify patients based on expression levels of 44 collagen genes and compared the prognosis and clinical characteristics between collagen subtypes. We then identified distinct transcriptomic and genetic alteration signatures for the subtypes. We analyzed the associations of collagen subtypes with the responses to chemotherapy, immunotherapy, and targeted therapy. We also established a platform-independent collagen-subtype predictor. We verified the findings in three validation cohorts (GSE84433, GSE62254, and GSE15459) and compared the collagen subtyping method with other molecular subtyping methods.

Results

We identified two subtypes of gastric adenocarcinoma: a high-expression collagen subtype (CS-H) and a low-expression collagen subtype (CS-L). Collagen subtype was an independent prognostic factor, with better overall survival in the CS-L subgroup. The inflammatory response, angiogenesis, and phosphoinositide 3-kinase (PI3K)/Akt pathways were transcriptionally active in the CS-H subtype, while DNA repair activity was significantly greater in the CS-L subtype. PIK3CA was frequently amplified in the CS-H subtype, while PIK3C2A, PIK3C2G, and PIK3R1 were frequently deleted in the CS-L subtype. CS-H subtype tumors were more sensitive to fluorouracil, while CS-L subtype tumors were more sensitive to immune checkpoint blockade. CS-L subtype was predicted to be more sensitive to HER2-targeted drugs, and CS-H subtype was predicted to be more sensitive to vascular endothelial growth factor and PI3K pathway-targeting drugs. Collagen subtyping also has the potential to be combined with existing molecular subtyping methods for better patient classification.

Conclusions

We classified gastric cancers into two subtypes based on collagen gene expression and validated these subtypes in three validation cohorts. The collagen subgroups differed in terms of prognosis, clinical characteristics, transc

背景 胃癌是一种高度异质性疾病,是个性化治疗的主要障碍。需要有效的免疫检查点阻断反应标志物来对患者进行精确分类。因此,我们根据胶原蛋白基因表达对胃癌患者进行了分类,以显示其预后和治疗反应。 方法 我们从四个队列中收集了 1250 例胃癌患者的数据。在 TCGA-STAD 队列中,我们根据 44 个胶原基因的表达水平使用共识聚类对患者进行了分层,并比较了不同胶原亚型的预后和临床特征。然后,我们确定了不同亚型的转录组和基因改变特征。我们分析了胶原蛋白亚型与化疗、免疫疗法和靶向疗法反应的关联。我们还建立了与平台无关的胶原亚型预测指标。我们在三个验证队列(GSE84433、GSE62254 和 GSE15459)中验证了这些发现,并将胶原亚型鉴定方法与其他分子亚型鉴定方法进行了比较。 结果 我们发现了两种胃腺癌亚型:高表达胶原亚型(CS-H)和低表达胶原亚型(CS-L)。胶原亚型是一个独立的预后因素,CS-L亚组的总生存率更高。在CS-H亚型中,炎症反应、血管生成和磷脂肌醇3-激酶(PI3K)/Akt通路转录活跃,而在CS-L亚型中,DNA修复活性显著增强。PIK3CA在CS-H亚型中经常扩增,而PIK3C2A、PIK3C2G和PIK3R1在CS-L亚型中经常缺失。CS-H亚型肿瘤对氟尿嘧啶更敏感,而CS-L亚型肿瘤对免疫检查点阻断剂更敏感。据预测,CS-L亚型对HER2靶向药物更敏感,而CS-H亚型对血管内皮生长因子和PI3K通路靶向药物更敏感。胶原蛋白亚型也有可能与现有的分子亚型方法相结合,以更好地对患者进行分类。 结论 我们根据胶原蛋白基因表达将胃癌分为两种亚型,并在三个验证队列中对这些亚型进行了验证。胶原亚型在预后、临床特征、转录组和基因改变方面存在差异。这些亚型与患者对化疗、免疫疗法和靶向疗法的反应密切相关。
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引用次数: 0
Synergistic effect of additional anlotinib and immunotherapy as second-line or later-line treatment in pancreatic cancer: A retrospective cohort study 胰腺癌二线或晚线治疗中追加安罗替尼和免疫疗法的协同效应:一项回顾性队列研究
Pub Date : 2024-05-14 DOI: 10.1002/cai2.123
Boyu Qin, Qi Xiong, Lingli Xin, Ke Li, Weiwei Shi, Qi Song, Qiong Sun, Jiakang Shao, Jing Zhang, Xiao Zhao, Jinyu Liu, Jinliang Wang, Bo Yang

Background

Pancreatic ductal adenocarcinoma (PDAC) is in urgent need of a second-line or later-line treatment strategy. We aimed to analyze the efficacy and safety of additional anlotinib, specifically anlotinib in combination with immunotherapy, in patients with PDAC who have failed first-line therapy.

Methods

Patients with pathological diagnosis of PDAC were additionally treated with anlotinib, and some patients were treated with anti-PD-1 agents at the same time, which could be retrospectively analyzed. The efficacy and safety of additional anlotinib were evaluated.

Results

A total of 23 patients were included. In patients treated with additional anlotinib, the overall median progression-free survival (PFS) was 1.8 months and the median overall survival (OS) was 6.3 months, regardless of anti-PD-1 agents. Among patients receiving additional anlotinib in combination with anti-PD-1 agents, median PFS and OS were 1.8 and 6.5 months, respectively. Adverse events (AEs) were observed in 16 patients (69.6%). In patients treated with additional anlotinib, the majority of AEs were grade 1–3. Univariate analysis revealed that patients with baseline red blood cell distribution width (RDW) <14% treated with additional anlotinib plus anti-PD-1 agents had significantly longer OS than patients with baseline RDW ≥14% (p = 0.025). Patients with additional anlotinib plus anti-PD-1 agents as second-line therapy had a longer OS than those treated as later-line therapy (p = 0.012). Multivariate analysis showed that baseline RDW was the only independent risk factor for OS (p = 0.042).

Conclusion

The combination of anlotinib and immunotherapy represents an effective add-on therapy with tolerable AEs as second- or later-line therapy in patients with PDAC, particularly in patients with baseline RDW <14%.

背景 胰腺导管腺癌(PDAC)急需二线或后线治疗策略。我们旨在分析一线治疗失败的 PDAC 患者额外使用安罗替尼,特别是安罗替尼联合免疫疗法的疗效和安全性。 方法 对病理诊断为 PDAC 的患者进行额外的安罗替尼治疗,部分患者同时接受了抗 PD-1 药物治疗,这些情况可进行回顾性分析。对追加使用安罗替尼的疗效和安全性进行了评估。 结果 共纳入23例患者。在接受额外安罗替尼治疗的患者中,无论是否使用抗PD-1药物,总体中位无进展生存期(PFS)为1.8个月,中位总生存期(OS)为6.3个月。在接受额外安罗替尼联合抗PD-1药物治疗的患者中,中位无进展生存期和中位总生存期分别为1.8个月和6.5个月。16名患者(69.6%)出现了不良事件(AEs)。在接受额外安罗替尼治疗的患者中,大多数 AE 为 1-3 级。单变量分析显示,基线红细胞分布宽度(RDW)<14%的患者接受额外安罗替尼加抗PD-1药物治疗的OS明显长于基线RDW≥14%的患者(p = 0.025)。作为二线疗法接受额外安罗替尼加抗PD-1药物治疗的患者的OS长于作为后线疗法治疗的患者(p = 0.012)。多变量分析显示,基线RDW是影响OS的唯一独立风险因素(p = 0.042)。 结论 作为PDAC患者的二线或晚线疗法,安罗替尼和免疫疗法的联合治疗是一种有效的附加疗法,且AEs可耐受,尤其是对于基线RDW为14%的患者。
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引用次数: 0
Novel progressive deep learning algorithm for uncovering multiple single nucleotide polymorphism interactions to predict paclitaxel clearance in patients with nonsmall cell lung cancer 揭示多种单核苷酸多态性相互作用的新型渐进式深度学习算法,用于预测非小细胞肺癌患者的紫杉醇清除率
Pub Date : 2024-05-12 DOI: 10.1002/cai2.110
Wei Chen, Haiyan Zhou, Mingyu Zhang, Yafei Shi, Taifeng Li, Di Qian, Jun Yang, Feng Yu, Guohui Li

Background

The rate at which the anticancer drug paclitaxel is cleared from the body markedly impacts its dosage and chemotherapy effectiveness. Importantly, paclitaxel clearance varies among individuals, primarily because of genetic polymorphisms. This metabolic variability arises from a nonlinear process that is influenced by multiple single nucleotide polymorphisms (SNPs). Conventional bioinformatics methods struggle to accurately analyze this complex process and, currently, there is no established efficient algorithm for investigating SNP interactions.

Methods

We developed a novel machine-learning approach called GEP-CSIs data mining algorithm. This algorithm, an advanced version of GEP, uses linear algebra computations to handle discrete variables. The GEP-CSI algorithm calculates a fitness function score based on paclitaxel clearance data and genetic polymorphisms in patients with nonsmall cell lung cancer. The data were divided into a primary set and a validation set for the analysis.

Results

We identified and validated 1184 three-SNP combinations that had the highest fitness function values. Notably, SERPINA1, ATF3 and EGF were found to indirectly influence paclitaxel clearance by coordinating the activity of genes previously reported to be significant in paclitaxel clearance. Particularly intriguing was the discovery of a combination of three SNPs in genes FLT1, EGF and MUC16. These SNPs-related proteins were confirmed to interact with each other in the protein–protein interaction network, which formed the basis for further exploration of their functional roles and mechanisms.

Conclusion

We successfully developed an effective deep-learning algorithm tailored for the nuanced mining of SNP interactions, leveraging data on paclitaxel clearance and individual genetic polymorphisms.

背景 抗癌药物紫杉醇从体内清除的速度对其剂量和化疗效果有明显影响。重要的是,紫杉醇的清除率因人而异,这主要是由于基因多态性造成的。这种代谢变异性来自一个非线性过程,受多个单核苷酸多态性(SNPs)的影响。传统的生物信息学方法难以准确分析这一复杂的过程,而且目前还没有一种有效的算法来研究 SNP 的相互作用。 方法 我们开发了一种名为 GEP-CSIs 数据挖掘算法的新型机器学习方法。该算法是 GEP 的高级版本,使用线性代数计算来处理离散变量。GEP-CSI 算法根据非小细胞肺癌患者的紫杉醇清除率数据和基因多态性计算适配函数得分。数据被分为初始集和验证集进行分析。 结果 我们发现并验证了 1184 个具有最高适配函数值的三SNP组合。值得注意的是,我们发现 SERPINA1、ATF3 和 EGF 通过协调之前报道的对紫杉醇清除率有重要影响的基因的活性,间接影响了紫杉醇的清除率。尤其引人关注的是发现了 FLT1、EGF 和 MUC16 基因中的三个 SNPs 组合。这些 SNPs 相关蛋白在蛋白相互作用网络中被证实相互影响,这为进一步探索它们的功能作用和机制奠定了基础。 结论 我们利用紫杉醇清除率和个体基因多态性的数据,成功开发了一种有效的深度学习算法,专门用于对 SNP 相互作用的细微挖掘。
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Cancer Innovation
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