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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
Cancer Innovation
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
Cancer Innovation
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。
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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
Cancer Innovation
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。
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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
Cancer Innovation
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。
{"title":"Identification of collagen subtypes of gastric cancer for distinguishing patient prognosis and therapeutic response","authors":"Di Wang,&nbsp;Jing Zhang,&nbsp;Jianchao Wang,&nbsp;Zhonglin Cai,&nbsp;Shanfeng Jin,&nbsp;Gang Chen","doi":"10.1002/cai2.125","DOIUrl":"https://doi.org/10.1002/cai2.125","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>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. <i>PIK3CA</i> was frequently amplified in the CS-H subtype, while <i>PIK3C2A</i>, <i>PIK3C2G</i>, and <i>PIK3R1</i> 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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>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","PeriodicalId":100212,"journal":{"name":"Cancer Innovation","volume":"3 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cai2.125","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140949137","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
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
Cancer Innovation
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
Cancer Innovation
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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引用次数: 0
Histone deacetylase 6 as a novel promising target to treat cardiovascular disease 组蛋白去乙酰化酶 6 是一种治疗心血管疾病的新型有望靶点
Cancer Innovation
Pub Date : 2024-05-07 DOI: 10.1002/cai2.114
Ya-Xi Wu, Bing-Qian Li, Xiao-Qian Yu, Yu-Lin Liu, Rui-Hao Chui, Kai Sun, Dian-Guang Geng, Li-Ying Ma

Histone deacetylase 6 (HDAC6) belongs to a class of epigenetic targets that have been found to be a key protein in the association between tumors and cardiovascular disease. Recent studies have focused on the crucial role of HDAC6 in regulating cardiovascular diseases such as atherosclerosis, myocardial infarction, myocardial hypertrophy, myocardial fibrosis, hypertension, pulmonary hypertension, and arrhythmia. Here, we review the association between HDAC6 and cardiovascular disease, the research progress of HDAC6 inhibitors in the treatment of cardiovascular disease, and discuss the feasibility of combining HDAC6 inhibitors with other therapeutic agents to treat cardiovascular disease.

组蛋白去乙酰化酶 6（HDAC6）属于一类表观遗传靶标，已被发现是肿瘤与心血管疾病相关的关键蛋白。最近的研究集中于 HDAC6 在调控动脉粥样硬化、心肌梗塞、心肌肥厚、心肌纤维化、高血压、肺动脉高压和心律失常等心血管疾病中的关键作用。在此，我们回顾了 HDAC6 与心血管疾病的关系、HDAC6 抑制剂治疗心血管疾病的研究进展，并探讨了 HDAC6 抑制剂与其他治疗药物联合治疗心血管疾病的可行性。
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引用次数: 0
Identification of a disulfidptosis-related prognostic signature for prediction of the effect of treatment in patients with endometrial carcinoma 确定与二硫化相关的预后特征，以预测子宫内膜癌患者的治疗效果
Cancer Innovation
Pub Date : 2024-04-23 DOI: 10.1002/cai2.120
Lu Peng, Yuan Gao, Zifeng Cao, Yingxin Pang

Background

Disulfide, an essential compounds family, has diverse biological activity and can affect the dynamic balance between physiological and pathological states. A recently published study found that aberrant accumulation of disulfide had a lethal effect on cells. This mechanism of cell death, named disulfidptosis, differs from other known cell death mechanisms, including cuproptosis, apoptosis, necroptosis, and pyroptosis. The relationship between disulfidptosis and development of cancer, in particular endometrial carcinoma, remains unclear.

Methods

To address this knowledge gap, we performed a preliminary analysis of samples from The Cancer Genome Atlas database. The samples were divided equally into a training group and a test group. A total of 2308 differentially expressed genes were extracted, and 11 were used to construct a prognostic model.

Results

Based on the risk score calculated using the prognostic model, the samples were divided into a high-risk group and a low-risk group. Survival time, tumor mutation burden, and microsatellite instability scores differed significantly between the two groups. Furthermore, a between-group difference in treatment effect was predicted. Comparison with other models in the literature indicated that this prognostic model had better predictive anility.

Conclusion

The results of this study provide a general framework for understanding the relationship between disulfidptosis and endometrial cancer that could be used for clinical evaluation and selection of appropriate personalized treatment strategies.

背景 二硫化物是一种重要的化合物家族，具有多种生物活性，可影响生理和病理状态之间的动态平衡。最近发表的一项研究发现，二硫化物的异常积累会对细胞产生致命影响。这种细胞死亡机制被命名为二硫化硫，它不同于其他已知的细胞死亡机制，包括杯突、凋亡、坏死和热凋亡。二硫化硫与癌症（尤其是子宫内膜癌）发展之间的关系仍不清楚。 方法 为了填补这一知识空白，我们对癌症基因组图谱数据库中的样本进行了初步分析。样本平均分为训练组和测试组。共提取了 2308 个差异表达基因，其中 11 个用于构建预后模型。 结果 根据预后模型计算出的风险评分，样本被分为高风险组和低风险组。两组样本的生存时间、肿瘤突变负荷和微卫星不稳定性评分差异显著。此外，还预测了治疗效果的组间差异。与其他文献中的模型比较表明，该预后模型具有更好的预测能力。 结论 本研究结果为了解二硫化硫与子宫内膜癌之间的关系提供了一个总体框架，可用于临床评估和选择适当的个性化治疗策略。
{"title":"Identification of a disulfidptosis-related prognostic signature for prediction of the effect of treatment in patients with endometrial carcinoma","authors":"Lu Peng,&nbsp;Yuan Gao,&nbsp;Zifeng Cao,&nbsp;Yingxin Pang","doi":"10.1002/cai2.120","DOIUrl":"https://doi.org/10.1002/cai2.120","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Disulfide, an essential compounds family, has diverse biological activity and can affect the dynamic balance between physiological and pathological states. A recently published study found that aberrant accumulation of disulfide had a lethal effect on cells. This mechanism of cell death, named disulfidptosis, differs from other known cell death mechanisms, including cuproptosis, apoptosis, necroptosis, and pyroptosis. The relationship between disulfidptosis and development of cancer, in particular endometrial carcinoma, remains unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>To address this knowledge gap, we performed a preliminary analysis of samples from The Cancer Genome Atlas database. The samples were divided equally into a training group and a test group. A total of 2308 differentially expressed genes were extracted, and 11 were used to construct a prognostic model.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Based on the risk score calculated using the prognostic model, the samples were divided into a high-risk group and a low-risk group. Survival time, tumor mutation burden, and microsatellite instability scores differed significantly between the two groups. Furthermore, a between-group difference in treatment effect was predicted. Comparison with other models in the literature indicated that this prognostic model had better predictive anility.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The results of this study provide a general framework for understanding the relationship between disulfidptosis and endometrial cancer that could be used for clinical evaluation and selection of appropriate personalized treatment strategies.</p>\u0000 </section>\u0000 </div>","PeriodicalId":100212,"journal":{"name":"Cancer Innovation","volume":"3 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cai2.120","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140639631","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
MAPK4 facilitates angiogenesis by inhibiting the ERK pathway in non-small cell lung cancer MAPK4 通过抑制 ERK 通路促进非小细胞肺癌的血管生成
Cancer Innovation
Pub Date : 2024-04-16 DOI: 10.1002/cai2.117
Jing Chen, Jing Yang, Yufang Liu, Xu Zhao, Juanjuan Zhao, Lin Tang, Mengmeng Guo, Ya Zhou, Chao Chen, Dongmei Li, Zhenke Wen, Guiyou Liang, Lin Xu

Background

Angiogenesis plays an important role in the occurrence and development of non-small cell lung cancer (NSCLC). The atypical mitogen-activated protein kinase 4 (MAPK4) has been shown to be involved in the pathogenesis of various diseases. However, the potential role of MAPK4 in the tumor angiogenesis of NSCLC remains unclear.

Methods

Adult male C57BL/6 wild-type mice were randomly divided into the control group and p-siMAPK4 intervention group, respectively. The cell proliferation was analyzed with flow cytometry and immunofluorescence staining. The vascular density in tumor mass was analyzed by immunofluorescence staining. The expressions of MAPK4 and related signaling molecules were detected by western blot analysis and immunofluorescence staining, and so on.

Results

We found that the expression of MAPK4, which was dominantly expressed in local endothelial cells (ECs), was correlated with tumor angiogenesis of NSCLC. Furthermore, MAPK4 silencing inhibited the proliferation and migration abilities of human umbilical vein ECs (HUVECs). Global gene analysis showed that MAPK4 silencing altered the expression of multiple genes related to cell cycle and angiogenesis pathways, and that MAPK4 silencing increased transduction of the extracellular regulated protein kinases 1/2 (ERK1/2) pathway but not Akt and c-Jun n-terminal kinase pathways. Further analysis showed that MAPK4 silencing inhibited the proliferation and migration abilities of HUVECs cultured in tumor cell supernatant, which was accompanied with increased transduction of the ERK1/2 pathway. Clinical data analysis suggested that the higher expression of MAPK4 and CD34 were associated with poor prognosis of patients with NSCLC. Targeted silencing of MAPK4 in ECs using small interfering RNA driven by the CD34 promoter effectively inhibited tumor angiogenesis and growth of NSCLC in vivo.

Conclusion

Our results reveal that MAPK4 plays an important role in the angiogenesis and development of NSCLC. MAPK4 may thus represent a new target for NSCLC.

背景 血管生成在非小细胞肺癌（NSCLC）的发生和发展中起着重要作用。非典型丝裂原活化蛋白激酶4（MAPK4）已被证明参与了多种疾病的发病机制。然而，MAPK4在NSCLC肿瘤血管生成中的潜在作用仍不清楚。 方法 将成年雄性 C57BL/6 野生型小鼠随机分为对照组和 p-siMAPK4 干预组。用流式细胞术和免疫荧光染色分析细胞增殖情况。用免疫荧光染色法分析瘤体的血管密度。通过 Western 印迹分析和免疫荧光染色等方法检测 MAPK4 及相关信号分子的表达。 结果 我们发现，主要在局部内皮细胞（ECs）中表达的 MAPK4 与 NSCLC 肿瘤血管生成相关。此外，沉默 MAPK4 可抑制人脐静脉内皮细胞（HUVECs）的增殖和迁移能力。全基因分析表明，沉默MAPK4改变了与细胞周期和血管生成通路相关的多个基因的表达，沉默MAPK4增加了细胞外调节蛋白激酶1/2（ERK1/2）通路的转导，但没有增加Akt和c-Jun n-末端激酶通路的转导。进一步分析表明，沉默 MAPK4 可抑制在肿瘤细胞上清液中培养的 HUVEC 的增殖和迁移能力，这与 ERK1/2 通路的转导增加有关。临床数据分析表明，MAPK4和CD34的高表达与NSCLC患者的不良预后有关。使用 CD34 启动子驱动的小干扰 RNA 靶向沉默 EC 中的 MAPK4 可有效抑制肿瘤血管生成和 NSCLC 在体内的生长。 结论 我们的研究结果表明，MAPK4 在 NSCLC 的血管生成和发展过程中发挥着重要作用。因此，MAPK4 可能是治疗 NSCLC 的一个新靶点。
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引用次数: 0
Cardiovascular toxicity with CTLA-4 inhibitors in cancer patients: A meta-analysis 癌症患者使用 CTLA-4 抑制剂的心血管毒性：荟萃分析
Cancer Innovation
Pub Date : 2024-04-16 DOI: 10.1002/cai2.116
Huiyi Liu, Lu Fu, Shuyu Jin, Xingdong Ye, Yanlin Chen, Sijia Pu, Yumei Xue

Background

With the emergence of cytotoxic T lymphocyte-associated protein-4 (CTLA-4) inhibitors, the outcomes of patients with malignant tumors have improved significantly. However, the incidence of cardiovascular adverse events has also increased, which can affect tumor treatment. In this study, we evaluated the incidence and severity of adverse cardiovascular events caused by CTLA-4 inhibitors by analyzing reported trials that involved CTLA-4 inhibitor therapy.

Methods

Randomized clinical trials published in English from January 1, 2013, to November 30, 2022, were searched using the Cochrane Library and PubMed databases. All included trials examined all grade and grades 3–5 cardiac and vascular adverse events. These involved comparisons of CTLA-4 inhibitors to placebo, CTLA-4 inhibitors plus chemotherapy to chemotherapy alone, CTLA-4 inhibitors combined with PD-1/PD-L1 inhibitors to PD-1/PD-L1 inhibitors alone, and CTLA-4 inhibitors plus target agent to PD-1/PD-L1 inhibitors plus target agent. The odds ratio (OR) and corresponding 95% confidence intervals (CIs) were calculated using the Mantel-Haenszel method.

Results

Overall, 20 trials were included. CTLA-4 inhibitors significantly increased the incidence of all-grade cardiovascular toxicity (OR = 1.33, 95% CI: 1.00–1.75, p = 0.05). The incidence of all-grade cardiovascular toxicity increased in malignant tumor patients who received single-agent CTLA-4 inhibitors (OR = 1.73, 95% CI: 1.13–2.65, p = 0.01), as well as the incidence rate of grades 3–5 cardiovascular adverse events (OR = 2.00, 95% CI: 1.08–3.70, p = 0.03). Compared with the non-CTLA-4 inhibitor group, CTLA-4 inhibitors plus chemotherapy, PD-1/PD-L1 inhibitors, or target agent did not significantly affect the incidence of cardiac and vascular toxicity. The incidence of grades 3–5 cardiac failure, hypertension, pericardial effusion, myocarditis, and atrial fibrillation were much higher among patients exposed to CTLA-4 inhibitor, but the data were not statistically significant.

Conclusion

Our findings suggest that the incidence rate of all cardiovascular toxicity and severe cardiovascular toxicity increased in patients who were administered CTLA-4 inhibitors. In addition, the risk of serious cardiovascular toxic events was independent of the type of adverse event. From these results, physicians should assess the benefits and risks of CTLA-4 inhibitors when treating malignanc

背景 随着细胞毒性 T 淋巴细胞相关蛋白-4（CTLA-4）抑制剂的出现，恶性肿瘤患者的治疗效果显著改善。然而，心血管不良事件的发生率也在增加，这可能会影响肿瘤的治疗。在本研究中，我们通过分析已报道的涉及 CTLA-4 抑制剂治疗的试验，评估了 CTLA-4 抑制剂引起的心血管不良事件的发生率和严重程度。 方法 使用 Cochrane Library 和 PubMed 数据库检索了 2013 年 1 月 1 日至 2022 年 11 月 30 日期间发表的英文随机临床试验。所有纳入的试验均检查了所有等级和 3-5 级心脏和血管不良事件。这些试验涉及CTLA-4抑制剂与安慰剂、CTLA-4抑制剂加化疗与单用化疗、CTLA-4抑制剂联合PD-1/PD-L1抑制剂与单用PD-1/PD-L1抑制剂、CTLA-4抑制剂加靶向药与PD-1/PD-L1抑制剂加靶向药的比较。采用Mantel-Haenszel方法计算了几率比（OR）和相应的95%置信区间（CI）。 结果 共纳入 20 项试验。CTLA-4抑制剂明显增加了全等级心血管毒性的发生率（OR = 1.33，95% CI：1.00-1.75，P = 0.05）。接受单药CTLA-4抑制剂治疗的恶性肿瘤患者全级别心血管毒性的发生率增加（OR = 1.73，95% CI：1.13-2.65，p = 0.01），3-5级心血管不良事件的发生率也增加（OR = 2.00，95% CI：1.08-3.70，p = 0.03）。与非CTLA-4抑制剂组相比，CTLA-4抑制剂加化疗、PD-1/PD-L1抑制剂或靶向药物对心脏和血管毒性的发生率没有显著影响。在接受 CTLA-4 抑制剂治疗的患者中，3-5 级心力衰竭、高血压、心包积液、心肌炎和心房颤动的发生率要高得多，但数据没有统计学意义。 结论 我们的研究结果表明，在使用 CTLA-4 抑制剂的患者中，所有心血管毒性和严重心血管毒性的发生率均有所增加。此外，严重心血管毒性事件的风险与不良事件的类型无关。根据这些结果，医生在治疗恶性肿瘤时应评估 CTLA-4 抑制剂的益处和风险。
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