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Communication between cancer cell subtypes by exosomes contributes to nasopharyngeal carcinoma metastasis and poor prognosis. 癌细胞亚型之间通过外泌体进行交流,导致鼻咽癌转移和预后不良。
IF 5.1 4区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-23 eCollection Date: 2024-09-01 DOI: 10.1093/pcmedi/pbae018
Hao-Jun Xie, Ming-Jie Jiang, Ke Jiang, Lin-Quan Tang, Qiu-Yan Chen, An-Kui Yang, Hai-Qiang Mai

Background: Intratumor heterogeneity is common in cancers, with different cell subtypes supporting each other to become more malignant. Nasopharyngeal carcinoma (NPC), a highly metastatic cancer, shows significant heterogeneity among its cells. This study investigates how NPC cell subtypes with varying metastatic potentials influence each other through exosome-transmitted molecules.

Methods: Exosomes were purified and characterized. MicroRNA expression was analyzed via sequencing and qRT-PCR. The effects of miR-30a-5p on migration, invasion, and metastasis were evaluated in vitro and in vivo. Its impact on desmoglein glycoprotein (DSG2) was assessed using dual-luciferase assays and Western blotting. Immunohistochemistry (IHC) and statistical models linked miR-30a-5p/DSG2 levels to patient prognosis.

Results: Different NPC cell subtypes transmit metastatic potential via exosomes. High-metastatic cells enhance the migration, invasion, and metastasis of low-metastatic cells through exosome-transmitted miR-30a-5p. Plasma levels of exosomal miR-30a-5p are reliable indicators of NPC prognosis. miR-30a-5p may promote metastasis by targeting DSG2 and modulating Wnt signaling. Plasma exosomal miR-30a-5p inversely correlates with DSG2 levels, predicting patient outcomes.

Conclusion: High-metastatic NPC cells can increase the metastatic potential of low-metastatic cells through exosome-transmitted miR-30a-5p, which is a valuable prognostic marker assessable via liquid biopsy.

背景:肿瘤内异质性在癌症中很常见,不同的细胞亚型相互支持,恶性程度更高。鼻咽癌(NPC)是一种高度转移性癌症,其细胞间存在显著的异质性。本研究探讨了具有不同转移潜能的鼻咽癌细胞亚型如何通过外泌体传递的分子相互影响:方法:纯化并鉴定外泌体。通过测序和 qRT-PCR 分析了微 RNA 的表达。在体外和体内评估了 miR-30a-5p 对迁移、侵袭和转移的影响。使用双荧光素酶测定法和 Western 印迹法评估了 miR-30a-5p 对去甲斑鸠蛋白糖蛋白(DSG2)的影响。免疫组织化学(IHC)和统计模型将 miR-30a-5p/DSG2 水平与患者预后联系起来:结果:不同的鼻咽癌细胞亚型通过外泌体传递转移潜能。结果:不同的鼻咽癌细胞亚型通过外泌体传递转移潜能。高转移细胞通过外泌体传递的 miR-30a-5p 增强低转移细胞的迁移、侵袭和转移。miR-30a-5p可能通过靶向DSG2和调节Wnt信号来促进转移。血浆外泌体miR-30a-5p与DSG2水平成反比,可预测患者的预后:结论:高转移性鼻咽癌细胞可通过外泌体传递的miR-30a-5p增加低转移性细胞的转移潜能,而miR-30a-5p是一种有价值的预后标志物,可通过液体活检进行评估。
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引用次数: 0
Fecal microbiota and metabolites in the pathogenesis and precision medicine for inflammatory bowel disease. 炎症性肠病发病机制和精准医疗中的粪便微生物群和代谢物。
IF 5.1 4区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-23 eCollection Date: 2024-09-01 DOI: 10.1093/pcmedi/pbae023
Long Ju, Zhimin Suo, Jian Lin, Zhanju Liu

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract, and its pathogenesis is believed to be associated with an imbalance between commensal organisms and the intestinal immune system. This imbalance is significantly influenced by the intestinal microbiota and metabolites and plays a critical role in maintaining intestinal mucosal homeostasis. However, disturbances in the intestinal microbiota cause dysregulated immune responses and consequently induce intestinal inflammation. Recent studies have illustrated the roles of the intestinal microbiota in the pathogenesis of IBD and underscored the potential of precision diagnosis and therapy. This work summarises recent progress in this field and particularly focuses on the application of the intestinal microbiota and metabolites in the precision diagnosis, prognosis assessment, treatment effectiveness evaluation, and therapeutic management of IBD.

炎症性肠病(IBD)是一种胃肠道慢性炎症性疾病,其发病机制被认为与共生生物和肠道免疫系统之间的失衡有关。这种失衡在很大程度上受到肠道微生物群和代谢产物的影响,并在维持肠道粘膜稳态方面发挥着关键作用。然而,肠道微生物群的紊乱会导致免疫反应失调,进而诱发肠道炎症。最近的研究表明了肠道微生物群在 IBD 发病机制中的作用,并强调了精准诊断和治疗的潜力。本研究总结了这一领域的最新进展,尤其关注肠道微生物群和代谢物在 IBD 的精准诊断、预后评估、疗效评价和治疗管理中的应用。
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引用次数: 0
Exosomal miRNAs and isomiRs: potential biomarkers for type 2 diabetes mellitus. 外泌体 miRNAs 和 isomiRs:2 型糖尿病的潜在生物标记物。
IF 5.1 4区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-20 eCollection Date: 2024-09-01 DOI: 10.1093/pcmedi/pbae021
Yong Ling Sou, William M Chilian, Wickneswari Ratnam, Shamsul Mohd Zain, Sharifah Zamiah Syed Abdul Kadir, Yan Pan, Yuh-Fen Pung

Type 2 diabetes mellitus (T2DM) is a metabolic disease that is characterized by chronic hyperglycaemia. MicroRNAs (miRNAs) are single-stranded, small non-coding RNAs that play important roles in post-transcriptional gene regulation. They are negative regulators of their target messenger RNAs (mRNAs), in which they bind either to inhibit mRNA translation, or to induce mRNA decay. Similar to proteins, miRNAs exist in different isoforms (isomiRs). miRNAs and isomiRs are selectively loaded into small extracellular vesicles, such as the exosomes, to protect them from RNase degradation. In T2DM, exosomal miRNAs produced by different cell types are transported among the primary sites of insulin action. These interorgan crosstalk regulate various T2DM-associated pathways such as adipocyte inflammation, insulin signalling, and β cells dysfunction among many others. In this review, we first focus on the mechanism of exosome biogenesis, followed by miRNA biogenesis and isomiR formation. Next, we discuss the roles of exosomal miRNAs and isomiRs in the development of T2DM and provide evidence from clinical studies to support their potential roles as T2DM biomarkers. Lastly, we highlight the use of exosomal miRNAs and isomiRs in personalized medicine, as well as addressing the current challenges and future opportunities in this field. This review summarizes how research on exosomal miRNAs and isomiRs has developed from the very basic to clinical applications, with the goal of advancing towards the era of personalized medicine.

2 型糖尿病(T2DM)是一种以慢性高血糖为特征的代谢性疾病。微小核糖核酸(miRNA)是单链的小型非编码核糖核酸,在转录后基因调控中发挥重要作用。它们是目标信使 RNA(mRNA)的负调控因子,与目标信使 RNA 结合可抑制 mRNA 翻译或诱导 mRNA 衰减。与蛋白质类似,miRNA 也存在不同的异构体(isomiRs)。miRNA 和 isomiRs 被选择性地装载到细胞外小泡(如外泌体)中,以防止它们被 RNase 降解。在 T2DM 中,由不同细胞类型产生的外泌体 miRNA 在胰岛素作用的主要部位之间传递。这些器官间的串联调节着各种与 T2DM 相关的通路,如脂肪细胞炎症、胰岛素信号传导、β 细胞功能障碍等。在这篇综述中,我们首先关注外泌体的生物生成机制,然后是 miRNA 的生物生成和异构体的形成。接下来,我们讨论了外泌体 miRNAs 和 isomiRs 在 T2DM 发病过程中的作用,并提供了临床研究证据来支持它们作为 T2DM 生物标志物的潜在作用。最后,我们强调了外泌体 miRNA 和异构体 Rs 在个性化医疗中的应用,并探讨了这一领域当前的挑战和未来的机遇。本综述总结了外泌体 miRNA 和异构体 Rs 的研究是如何从基础研究发展到临床应用的,其目标是迈向个性化医疗时代。
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引用次数: 0
Phenotypic age mediates effects of Life's Essential 8 on reduced mortality risk in US adults. 表型年龄是 "人生必修 8 "对降低美国成年人死亡风险影响的中介。
IF 5.1 4区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-16 eCollection Date: 2024-09-01 DOI: 10.1093/pcmedi/pbae019
Yuxuan Zhao, Haiming Yang, Rong Jiao, Yueqing Wang, Meng Xiao, Mingyu Song, Huan Yu, Chunxiao Liao, Yuanjie Pang, Wenjing Gao, Tao Huang, Canqing Yu, Jun Lv, Shengxu Li, Lu Qi, Liming Li, Dianjianyi Sun

Objective: This study aimed to find out whether phenotypic age could mediate the protective effects of a healthy lifestyle on mortality.

Methods: We included adult participants with available data for individual phenotypic age (PhenoAge) and Life's Essential 8 (LE8) scores from the National Health and Nutrition Examination Survey 2005-2010 (three cycles) and linked mortality records until 31 December 2019. Adjusted hazard ratios (HR) were estimated to evaluate the associations of PhenoAge and LE8 scores with all-cause and cardiovascular mortality risk. Mediation analyses were performed to estimate the proportional contribution of PhenoAge to the effect of LE8 on mortality risks.

Results: A 1-year increment in PhenoAge was associated with a higher risk of all-cause (HR = 1.04 [95% confidence interval, 1.04-1.05]) and cardiovascular (HR = 1.04 [95% confidence interval, 1.04-1.05]) mortality, independent of chronological age, demographic characteristics, and disease history. High level of LE8 (score: 80-100) was associated with a 3.30-year younger PhenoAge. PhenoAge was estimated to mediate 36 and 22% of the effect of LE8 on all-cause and cardiovascular mortality, respectively (all P < 0.001). As for single-metric scores of LE8, PhenoAge mediated 30%, 11%, 9%, and 7% of the effects of the healthy diet, smoking status, blood pressure, and physical activity on all-cause mortality risk, respectively (all P < 0.05).

Conclusion: Adherence to LE8 recommendations slows phenotypic aging. PhenoAge could mediate the effect of LE8 on mortality risk.

研究目的本研究旨在探究表型年龄是否能调节健康生活方式对死亡率的保护作用:我们纳入了2005-2010年全国健康与营养调查(三个周期)中有个人表型年龄(PhenoAge)和生命必备8(LE8)评分数据的成年参与者,并链接了截至2019年12月31日的死亡记录。估算了调整后的危险比(HR),以评估 PhenoAge 和 LE8 分数与全因和心血管死亡风险的关联。进行了中介分析,以估算 PhenoAge 对 LE8 对死亡风险影响的比例贡献:结果:PhenoAge 每增加 1 年,全因(HR = 1.04 [95% 置信区间,1.04-1.05])和心血管(HR = 1.04 [95% 置信区间,1.04-1.05])死亡风险就会增加,与实际年龄、人口特征和疾病史无关。LE8水平高(80-100分)与PhenoAge年轻3.30岁有关。据估计,LE8 对全因死亡率和心血管死亡率的影响中,年龄分别占 36% 和 22%(均为 P P P 结论):遵守LE8的建议可延缓表型老化。PhenoAge可以调节LE8对死亡风险的影响。
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引用次数: 0
Multidisciplinary treatment and immunotherapy improved the prognosis of advanced small intestine sarcomatoid carcinoma 多学科治疗和免疫疗法改善了晚期小肠肉瘤样癌的预后
IF 5.1 4区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-07-02 DOI: 10.1093/pcmedi/pbae014
Bo Wang, Meng Qiu
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引用次数: 0
Deep learning-based multi-modal data integration enhancing breast cancer disease-free survival prediction. 基于深度学习的多模态数据整合提高了乳腺癌无病生存率预测能力。
IF 5.1 4区 医学 Q1 Medicine Pub Date : 2024-05-29 eCollection Date: 2024-06-01 DOI: 10.1093/pcmedi/pbae012
Zehua Wang, Ruichong Lin, Yanchun Li, Jin Zeng, Yongjian Chen, Wenhao Ouyang, Han Li, Xueyan Jia, Zijia Lai, Yunfang Yu, Herui Yao, Weifeng Su

Background: The prognosis of breast cancer is often unfavorable, emphasizing the need for early metastasis risk detection and accurate treatment predictions. This study aimed to develop a novel multi-modal deep learning model using preoperative data to predict disease-free survival (DFS).

Methods: We retrospectively collected pathology imaging, molecular and clinical data from The Cancer Genome Atlas and one independent institution in China. We developed a novel Deep Learning Clinical Medicine Based Pathological Gene Multi-modal (DeepClinMed-PGM) model for DFS prediction, integrating clinicopathological data with molecular insights. The patients included the training cohort (n = 741), internal validation cohort (n = 184), and external testing cohort (n = 95).

Result: Integrating multi-modal data into the DeepClinMed-PGM model significantly improved area under the receiver operating characteristic curve (AUC) values. In the training cohort, AUC values for 1-, 3-, and 5-year DFS predictions increased to 0.979, 0.957, and 0.871, while in the external testing cohort, the values reached 0.851, 0.878, and 0.938 for 1-, 2-, and 3-year DFS predictions, respectively. The DeepClinMed-PGM's robust discriminative capabilities were consistently evident across various cohorts, including the training cohort [hazard ratio (HR) 0.027, 95% confidence interval (CI) 0.0016-0.046, P < 0.0001], the internal validation cohort (HR 0.117, 95% CI 0.041-0.334, P < 0.0001), and the external cohort (HR 0.061, 95% CI 0.017-0.218, P < 0.0001). Additionally, the DeepClinMed-PGM model demonstrated C-index values of 0.925, 0.823, and 0.864 within the three cohorts, respectively.

Conclusion: This study introduces an approach to breast cancer prognosis, integrating imaging and molecular and clinical data for enhanced predictive accuracy, offering promise for personalized treatment strategies.

背景:乳腺癌的预后往往不佳,因此需要进行早期转移风险检测和准确的治疗预测。本研究旨在利用术前数据开发一种新型多模态深度学习模型,以预测无病生存期(DFS):我们回顾性地收集了来自癌症基因组图谱和中国一家独立机构的病理成像、分子和临床数据。我们开发了一种新型的基于深度学习的临床医学病理基因多模态(DeepClinMed-PGM)模型,将临床病理数据与分子洞察力相结合,用于预测无病生存期。患者包括训练队列(n = 741)、内部验证队列(n = 184)和外部测试队列(n = 95):结果:将多模态数据整合到DeepClinMed-PGM模型中能显著提高接收者工作特征曲线下面积(AUC)值。在训练队列中,1 年、3 年和 5 年 DFS 预测的 AUC 值分别增至 0.979、0.957 和 0.871,而在外部测试队列中,1 年、2 年和 3 年 DFS 预测的 AUC 值分别达到 0.851、0.878 和 0.938。DeepClinMed-PGM 强大的判别能力在包括训练队列在内的不同队列中始终如一地表现出来[危险比(HR)0.027,95% 置信区间(CI)0.0016-0.046,P P P 结论:这项研究介绍了一种乳腺癌预后的方法,它整合了成像、分子和临床数据,提高了预测的准确性,为个性化治疗策略带来了希望。
{"title":"Deep learning-based multi-modal data integration enhancing breast cancer disease-free survival prediction.","authors":"Zehua Wang, Ruichong Lin, Yanchun Li, Jin Zeng, Yongjian Chen, Wenhao Ouyang, Han Li, Xueyan Jia, Zijia Lai, Yunfang Yu, Herui Yao, Weifeng Su","doi":"10.1093/pcmedi/pbae012","DOIUrl":"10.1093/pcmedi/pbae012","url":null,"abstract":"<p><strong>Background: </strong>The prognosis of breast cancer is often unfavorable, emphasizing the need for early metastasis risk detection and accurate treatment predictions. This study aimed to develop a novel multi-modal deep learning model using preoperative data to predict disease-free survival (DFS).</p><p><strong>Methods: </strong>We retrospectively collected pathology imaging, molecular and clinical data from The Cancer Genome Atlas and one independent institution in China. We developed a novel Deep Learning Clinical Medicine Based Pathological Gene Multi-modal (DeepClinMed-PGM) model for DFS prediction, integrating clinicopathological data with molecular insights. The patients included the training cohort (<i>n</i> = 741), internal validation cohort (<i>n</i> = 184), and external testing cohort (<i>n</i> = 95).</p><p><strong>Result: </strong>Integrating multi-modal data into the DeepClinMed-PGM model significantly improved area under the receiver operating characteristic curve (AUC) values. In the training cohort, AUC values for 1-, 3-, and 5-year DFS predictions increased to 0.979, 0.957, and 0.871, while in the external testing cohort, the values reached 0.851, 0.878, and 0.938 for 1-, 2-, and 3-year DFS predictions, respectively. The DeepClinMed-PGM's robust discriminative capabilities were consistently evident across various cohorts, including the training cohort [hazard ratio (HR) 0.027, 95% confidence interval (CI) 0.0016-0.046, <i>P</i> < 0.0001], the internal validation cohort (HR 0.117, 95% CI 0.041-0.334, <i>P</i> < 0.0001), and the external cohort (HR 0.061, 95% CI 0.017-0.218, <i>P</i> < 0.0001). Additionally, the DeepClinMed-PGM model demonstrated C-index values of 0.925, 0.823, and 0.864 within the three cohorts, respectively.</p><p><strong>Conclusion: </strong>This study introduces an approach to breast cancer prognosis, integrating imaging and molecular and clinical data for enhanced predictive accuracy, offering promise for personalized treatment strategies.</p>","PeriodicalId":33608,"journal":{"name":"Precision Clinical Medicine","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11190375/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141443434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Depletion of squalene epoxidase in synergy with glutathione peroxidase 4 inhibitor RSL3 overcomes oxidative stress resistance in lung squamous cell carcinoma 消耗角鲨烯环氧化物酶与谷胱甘肽过氧化物酶 4 抑制剂 RSL3 协同作用,可克服肺鳞状细胞癌的氧化应激抗性
IF 5.3 4区 医学 Q1 Medicine Pub Date : 2024-05-08 DOI: 10.1093/pcmedi/pbae011
Guo Li, Lu Chen, Hua Bai, Li Zhang, Jie Wang, Weimin Li
Lung squamous cell carcinoma (LUSC) lacks effective targeted therapies and has a poor prognosis. Disruption of squalene epoxidase (SQLE) has been implicated in metabolic disorders and cancer. However, the role of SQLE as a monooxygenase involved in oxidative stress remains unclear. Here, we investigated the unique role of SQLE expression in the diagnosis and prognosis prediction of LUSC. Knockdown of SQLE or treatment with the SQLE inhibitor terbinafine (TBF) can suppress the proliferation of LUSC cells by inducing apoptosis and reactive oxygen species (ROS) accumulation. However, depletion of SQLE also results in the impairment of lipid peroxidation and ferroptosis resistance such as upregulation of glutathione peroxidase 4 (GPX4). Therefore, prevention of SQLE in synergy with GPX4 inhibitor RSL3 effectively mitigates the proliferation and growth of LUSC. Our study indicates that the low expression of SQLE employs the adaptive survival through regulating the balance of apoptosis and resistance of ferroptosis. In future, the combinational therapy of targeting SQLE and ferroptosis could be a promising approach in treating LUSC.
肺鳞状细胞癌(LUSC)缺乏有效的靶向疗法,预后较差。角鲨烯环氧化酶(SQLE)的破坏与代谢紊乱和癌症有关。然而,SQLE 作为一种参与氧化应激的单氧化酶,其作用仍不清楚。在此,我们研究了SQLE表达在LUSC诊断和预后预测中的独特作用。敲除SQLE或用SQLE抑制剂特比萘芬(TBF)治疗可通过诱导细胞凋亡和活性氧(ROS)积累来抑制LUSC细胞的增殖。然而,SQLE 的耗竭也会导致脂质过氧化和铁变态反应抗性受损,如谷胱甘肽过氧化物酶 4(GPX4)上调。因此,预防 SQLE 与 GPX4 抑制剂 RSL3 协同作用可有效缓解 LUSC 的增殖和生长。我们的研究表明,SQLE的低表达通过调节凋亡和抗铁蛋白沉积的平衡来实现适应性生存。未来,针对SQLE和铁凋亡的联合疗法可能是治疗LUSC的一种有前景的方法。
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引用次数: 0
TP53-specific mutations serve as a potential biomarker for homologous recombination deficiency in breast cancer: a clinical next-generation sequencing study TP53特异性突变是乳腺癌同源重组缺陷的潜在生物标志物:一项临床新一代测序研究
IF 5.3 4区 医学 Q1 Medicine Pub Date : 2024-04-09 DOI: 10.1093/pcmedi/pbae009
Yongsheng Huang, Shuwei Ren, Li Ding, Yuanling Jiang, Jiahuan Luo, Jinghua Huang, Xinke Yin, Jianli Zhao, Sha Fu, Jianwei Liao
TP53 mutations and homologous recombination deficiency (HRD) occur frequently in breast cancer. However, the characteristics of TP53 pathogenic mutations in breast cancer patients with/without HRD are not clear. Both tumor and paired blood DNA from 119 breast cancer patients were performed clinical next-generation sequencing (NGS) by a 520-gene panel. Mutations, tumor mutation burden (TMB), and genomic HRD scores were assessed from NGS data. All TP53 pathogenic mutations in patients were the somatic origin, which was associated with the protein expression of estrogen receptor and progestogen receptor. Compared to patients without TP53 pathologic mutations, patients with TP53 pathologic mutations had higher levels of HRD scores and different genomic alterations. The frequency of TP53 pathologic mutation was higher in the HRD-High group (HRD score≥42) relative to that in the HRD-Low group (HRD score<42). TP53 has different mutational characteristics between the HRD-Low and HRD-High groups. TP53-specific mutation subgroups had diverse genomic features and TMB. Notably, TP53 pathogenic mutations predicted the HRD status of breast cancer patients with an AUC of 0.61. TP53-specific mutations, namely HRD-Low mutation, HRD-High mutation, and HRD common mutation, predicted the HRD status of breast cancer patients with AUC values of 0.32, 0.72, and 0.58, respectively. Interestingly, TP53 HRD-High mutation and HRD common mutation combinations showed the highest AUC values (0.80) in predicting HRD status. TP53-specific mutation combinations predict the HRD status of patients, indicating that TP53 pathogenic mutations could serve as a potential biomarker for PARP inhibitors in breast cancer patients.
TP53突变和同源重组缺陷(HRD)经常发生在乳腺癌中。然而,有/无HRD的乳腺癌患者中TP53致病突变的特征尚不清楚。 研究人员对 119 名乳腺癌患者的肿瘤和配对血液 DNA 进行了临床新一代测序(NGS),检测了 520 个基因。根据 NGS 数据评估了突变、肿瘤突变负荷(TMB)和基因组 HRD 评分。 患者的所有 TP53 致病突变均为体细胞突变,与雌激素受体和孕激素受体的蛋白表达有关。与无 TP53 病理突变的患者相比,有 TP53 病理突变的患者的 HRD 评分更高,基因组改变也不同。相对于HRD-Low组(HRD评分<42),HRD-High组(HRD评分≥42)的TP53病理突变频率更高。TP53在HRD-低组和HRD-高组之间具有不同的突变特征。TP53特异性突变亚组具有不同的基因组特征和TMB。值得注意的是,TP53致病突变可预测乳腺癌患者的HRD状态,AUC为0.61。TP53特异性突变,即HRD-低突变、HRD-高突变和HRD常见突变,可预测乳腺癌患者的HRD状态,AUC值分别为0.32、0.72和0.58。有趣的是,TP53 HRD-High突变和HRD常见突变组合在预测HRD状态方面显示出最高的AUC值(0.80)。 TP53特异性突变组合可预测患者的HRD状态,这表明TP53致病突变可作为乳腺癌患者使用PARP抑制剂的潜在生物标志物。
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引用次数: 0
Genome and clonal hematopoiesis stability contrasts with immune, cfDNA, mitochondrial, and telomere length changes during short duration spaceflight. 基因组和克隆造血的稳定性与短时太空飞行期间免疫、cfDNA、线粒体和端粒长度的变化形成鲜明对比。
IF 5.3 4区 医学 Q1 Medicine Pub Date : 2024-04-08 eCollection Date: 2024-03-01 DOI: 10.1093/pcmedi/pbae007
J Sebastian Garcia-Medina, Karolina Sienkiewicz, S Anand Narayanan, Eliah G Overbey, Kirill Grigorev, Krista A Ryon, Marissa Burke, Jacqueline Proszynski, Braden Tierney, Caleb M Schmidt, Nuria Mencia-Trinchant, Remi Klotz, Veronica Ortiz, Jonathan Foox, Christopher Chin, Deena Najjar, Irina Matei, Irenaeus Chan, Carlos Cruchaga, Ashley Kleinman, JangKeun Kim, Alexander Lucaci, Conor Loy, Omary Mzava, Iwijn De Vlaminck, Anvita Singaraju, Lynn E Taylor, Julian C Schmidt, Michael A Schmidt, Kelly Blease, Juan Moreno, Andrew Boddicker, Junhua Zhao, Bryan Lajoie, Andrew Altomare, Semyon Kruglyak, Shawn Levy, Min Yu, Duane C Hassane, Susan M Bailey, Kelly Bolton, Jaime Mateus, Christopher E Mason

Background: The Inspiration4 (I4) mission, the first all-civilian orbital flight mission, investigated the physiological effects of short-duration spaceflight through a multi-omic approach. Despite advances, there remains much to learn about human adaptation to spaceflight's unique challenges, including microgravity, immune system perturbations, and radiation exposure.

Methods: To provide a detailed genetics analysis of the mission, we collected dried blood spots pre-, during, and post-flight for DNA extraction. Telomere length was measured by quantitative PCR, while whole genome and cfDNA sequencing provided insight into genomic stability and immune adaptations. A robust bioinformatic pipeline was used for data analysis, including variant calling to assess mutational burden.

Result: Telomere elongation occurred during spaceflight and shortened after return to Earth. Cell-free DNA analysis revealed increased immune cell signatures post-flight. No significant clonal hematopoiesis of indeterminate potential (CHIP) or whole-genome instability was observed. The long-term gene expression changes across immune cells suggested cellular adaptations to the space environment persisting months post-flight.

Conclusion: Our findings provide valuable insights into the physiological consequences of short-duration spaceflight, with telomere dynamics and immune cell gene expression adapting to spaceflight and persisting after return to Earth. CHIP sequencing data will serve as a reference point for studying the early development of CHIP in astronauts, an understudied phenomenon as previous studies have focused on career astronauts. This study will serve as a reference point for future commercial and non-commercial spaceflight, low Earth orbit (LEO) missions, and deep-space exploration.

背景:Inspiration4(I4)任务是首次全民用轨道飞行任务,它通过多原子方法研究了短期太空飞行的生理影响。尽管取得了进展,但在人类适应太空飞行的独特挑战(包括微重力、免疫系统扰动和辐射暴露)方面仍有许多东西需要学习:为了对飞行任务进行详细的遗传学分析,我们收集了飞行前、飞行中和飞行后的干血迹,以提取 DNA。通过定量 PCR 测量端粒长度,同时进行全基因组和 cfDNA 测序,以深入了解基因组稳定性和免疫适应性。数据分析使用了强大的生物信息学管道,包括评估突变负担的变异调用:结果:端粒在太空飞行期间延长,返回地球后缩短。无细胞DNA分析显示飞行后免疫细胞特征增加。没有观察到明显的不确定潜能克隆造血(CHIP)或全基因组不稳定性。免疫细胞基因表达的长期变化表明,细胞对太空环境的适应在飞行数月后仍然存在:我们的研究结果为了解短时太空飞行的生理后果提供了有价值的见解,端粒动态和免疫细胞基因表达适应太空飞行,并在返回地球后持续存在。CHIP测序数据将成为研究宇航员CHIP早期发展的参考点,由于以往的研究主要集中在职业宇航员身上,因此对这一现象的研究不够。这项研究将成为未来商业和非商业航天飞行、低地球轨道(LEO)任务和深空探索的参考点。
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引用次数: 0
Association of the immediate perioperative dynamics of circulating DNA levels and neutrophil extracellular traps formationin cancer patients 癌症患者围手术期循环 DNA 水平的即时动态变化与中性粒细胞胞外捕获物形成的关系
IF 5.3 4区 医学 Q1 Medicine Pub Date : 2024-03-27 DOI: 10.1093/pcmedi/pbae008
Andrei Kudriavtsev, B. Pastor, Alexia Mirandola, E. Pisareva, Y. Gricourt, Xavier Capdevila, Alain R. Thierry, Philippe Cuvillon
Elevated circulating DNA (cirDNA) concentrations were found to be associated with trauma or tissue damage which suggests involvement of inflammation or cell death in post-operative cirDNA release. We carried out the first prospective, multicenter study of the dynamics of cirDNA and neutrophil extracellular traps (NETs) markers during the perioperative period from 24 hours before surgery up to 72 hours after curative surgery in cancer patients. We examined the plasma levels of two NETs protein markers (myeloperoxidase (MPO) and neutrophil elastase (NE)), as well as levels of cirDNA of nuclear (cir-nDNA) and mitochondrial (cir-mtDNA) origins in 29 patients colon, prostate and breast cancer and in 114 healthy individuals (HI). The synergistic analytical information provided by these markers revealed that: (i) NETs formation contributes to post-surgery conditions; (ii) post-surgery cir-nDNA levels were highly associated with NE and MPO in colon cancer (r=0.60 (p<0.001) and r=0.53 (p<0.01), respectively), but not in prostate and breast cancer; (iii) each tumor type shows a specific pattern of cir-nDNA and NETs marker dynamics, but overall the pre- and post-surgery median values of cir-nDNA, NE, and MPO were significantly higher in cancer patients than in HI. Taken as a whole, our work reveals the association of NETs formation with the elevated cir-nDNA release during a cancer patient's perioperative period, depending on surgical procedure or cancer type. By contrast, cir-mtDNA is poorly associated with NETs formation in the studied perioperative period, which would appear to indicate a different mechanism of release or suggest mitochondria dysfunction.
研究发现,循环 DNA(cirDNA)浓度升高与创伤或组织损伤有关,这表明炎症或细胞死亡参与了术后 cirDNA 的释放。我们对癌症患者从手术前24小时到治愈手术后72小时的围手术期cirDNA和中性粒细胞胞外捕获物(NETs)标记物的动态进行了首次前瞻性多中心研究。 我们检测了 29 名结肠癌、前列腺癌和乳腺癌患者以及 114 名健康人(HI)血浆中两种 NETs 蛋白标记物(髓过氧化物酶 (MPO) 和中性粒细胞弹性蛋白酶 (NE))的水平,以及来源于核(cir-nDNA)和线粒体(cir-mtDNA)的 cirDNA 水平。 这些标记物提供的协同分析信息表明(i) NETs 的形成与手术后的情况有关;(ii) 结肠癌患者手术后的 cir-nDNA 水平与 NE 和 MPO 高度相关(分别为 r=0.60 (p<0.001) 和 r=0.53 (p<0. 01)),但与 NE 和 MPO 无关。01)),但在前列腺癌和乳腺癌中没有相关性;(iii) 每种肿瘤类型都显示出特定的 cir-nDNA 和 NETs 标记物动态模式,但总体而言,癌症患者手术前后的 cir-nDNA、NE 和 MPO 中位值明显高于 HI。 总的来说,我们的研究揭示了癌症患者围手术期cir-nDNA释放量升高与NETs形成的关系,这取决于手术过程或癌症类型。相比之下,在所研究的围手术期,cir-mtDNA与NET的形成关系不大,这似乎表明了一种不同的释放机制或线粒体功能障碍。
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Precision Clinical Medicine
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