Translational Oncology最新文献_第3页

METTL3 methylated KIF15 promotes nasopharyngeal carcinoma progression and radiation resistance by blocking ATG7-mediated autophagy through the activation of STAT3 pathway METTL3甲基化的KIF15通过激活STAT3通路阻断ATG7介导的自噬作用，从而促进鼻咽癌的进展和耐辐射性

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2024-11-05 DOI: 10.1016/j.tranon.2024.102161

Siwei Li , Shuibin Wang , Lu Zhang , Xiaofeng Wu , Longfu Tian , Jiahua Zou , Guoliang Pi

Background

Resistance to radiotherapy is a major component in the failure of nasopharyngeal carcinoma (NPC) treatment. Enhancing autophagy in nasopharyngeal carcinoma may increase its radiation sensitivity, making it critical to find autophagy-modulating targets.

Methods

The level of KIF15 was determined in NPC patients. Then, radiation-resistant NPC cells were produced to explore the mechanism in NPC. KIF15 was suppressed, and cell function and autophagy-related variables were examined in radiation-resistant NPC cells. Then the autophagy pathway was blocked, and the link between KIF15 and autophagy was confirmed. Finally, an NPC murine model was established, with tumors implanted in aberrant sites, and the relationship discovered at the cell level was confirmed in vivo. All statistical significance was determined using the student's t-test and one-way ANOVA.

Results

Elevated amounts of KIF15 were discovered to be significantly expressed in NPC tissues and played a role in the radioresistance of NPC, a phenomenon attributed to METTL3-mediated m6A methylation. Blocking KIF15 resulted in decreased cell proliferation, increased cell death, and the activation of autophagy, ultimately making NPC more sensitive to radiation. This also resulted in decreased tumor development and increased levels of autophagy and apoptosis in vivo KIF15 interacted with STAT3, retaining it in the cytoplasm. Overexpression of STAT3 reversed the inhibitory effects of KIF15 knockdown on NPC and also reversed the influence of sh-KIF15 on autophagy activation. Inhibition of KIF15 decreased the inhibitory effect of STAT3 on ATG7, thereby upregulating autophagy activation in radio-resistant NPC cells.

Conclusion

The increased expression of KIF15 was found to be associated with the progression of NPC and play a role in the development of radioresistance in NPC. Inhibiting KIF15 was shown to impede tumor growth and improve the sensitivity of NPC to radiotherapy by triggering autophagy via the STAT3/ATG7 pathway.

背景放疗抵抗是鼻咽癌（NPC）治疗失败的主要原因。方法测定鼻咽癌患者体内 KIF15 的水平。方法测定鼻咽癌患者体内 KIF15 的水平，然后制备抗辐射鼻咽癌细胞以探索鼻咽癌的机制。方法测定了鼻咽癌患者体内 KIF15 的水平，然后制备了耐辐射鼻咽癌细胞，以探索鼻咽癌的机制。然后阻断自噬途径，证实了 KIF15 与自噬之间的联系。最后，建立了一个鼻咽癌小鼠模型，将肿瘤植入异常部位，并在体内证实了在细胞水平发现的关系。结果发现 KIF15 在鼻咽癌组织中大量表达，并在鼻咽癌的放射抗性中发挥作用，这一现象归因于 METTL3 介导的 m6A 甲基化。阻断 KIF15 会导致细胞增殖减少、细胞死亡增加和自噬激活，最终使鼻咽癌对辐射更加敏感。KIF15 与 STAT3 相互作用，将其保留在细胞质中。STAT3 的过表达逆转了 KIF15 敲除对鼻咽癌的抑制作用，也逆转了 sh-KIF15 对自噬激活的影响。抑制 KIF15 可降低 STAT3 对 ATG7 的抑制作用，从而上调耐放射 NPC 细胞的自噬激活。抑制KIF15可通过STAT3/ATG7途径触发自噬，从而阻碍肿瘤生长并提高鼻咽癌对放疗的敏感性。

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引用次数: 0

New combined treatments, surgery and high-dose-rate interventional radiotherapy (brachytherapy), in advanced ocular surface and eyelid cancers 针对晚期眼表癌和眼睑癌的新型综合疗法--手术和高剂量率介入放射治疗（近距离放疗）。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2024-11-05 DOI: 10.1016/j.tranon.2024.102160

Bruno Fionda , Monica Maria Pagliara , Maria Grazia Sammarco , Francesco Pastore , Federico Giannuzzi , Giovanni Cuffaro , Flavia Quaranta Leoni , Luca Tagliaferri , Gustavo Savino

Purpose

To evaluate the clinicopathological characteristics and the effectiveness of post-operative high-dose-rate (HDR) interventional radiotherapy (IRT - brachytherapy) in managing advanced ocular surface squamous neoplasia (OSSN) and eyelid tumors.

Methods

Nineteen patients with advanced malignancies affecting the ocular surface (stage ≥ T2) and eyelids (staging ≥ T3) were enrolled. Post-operative HDR-IRT treatment followed surgery after multidisciplinary discussion. In our series a total dose of 49 Gy was administered in 14 fractions of 3.5 Gy each, 2 doses per day. Local disease control is the study's main outcome. Death rate, total survival, disease-free survival, and toxicity are secondary outcomes.

Results

Local recurrence was observed in 4 cases, 2 were conjunctival melanomas and 2 were conjunctival squamous cell carcinoma. The median OS was 56.3 months. The 12, 24 and 36 months survival rate was respectively 100.00% (IQR: 100.00% - 100.00%), 100.00% (IQR: 100.00% - 100.00%), 100.00% (IQR: 100.00% - 100.00%) respectively . The median DFS was 56.3 months. The 12, 24 and 36 months disease survival rate was respectively 85.71% (IQR: 69.21% - 100.00%), 68.57% (IQR: 42.11% - 100.00%), 68.57% (IQR: 42.11% - 100.00%) respectively. In eyelid tumors, madarosis and eyelid abnormalities are the main side effects, while in OSSNs, dry eye symptoms are frequently reported.

Conclusion

Postoperative HDR-IRT has been effective in advanced eyelid cancers control. More challenging appears instead an effective treatment of advanced OSSNs, particularly conjunctival melanomas. Multicenter studies are needed to get a larger patient sample and to evaluate different radiotherapy dosages by different histologic and T types of tumors.

目的：评估晚期眼表鳞状肿瘤（OSSN）和眼睑肿瘤的临床病理特征以及术后高剂量率（HDR）介入放射治疗（IRT-近距离放射治疗）的疗效：方法：19 名患有晚期眼表恶性肿瘤（分期≥ T2）和眼睑恶性肿瘤（分期≥ T3）的患者入选。经多学科讨论后，患者在手术后接受 HDR-IRT 治疗。在我们的系列研究中，总剂量为 49 Gy，分 14 次进行，每次 3.5 Gy，每天 2 次。局部疾病控制是研究的主要结果。死亡率、总生存率、无病生存率和毒性是次要结果：结果：4例观察到局部复发，其中2例为结膜黑色素瘤，2例为结膜鳞状细胞癌。中位生存期为 56.3 个月。12、24和36个月的生存率分别为100.00%（IQR：100.00% - 100.00%）、100.00%（IQR：100.00% - 100.00%）、100.00%（IQR：100.00% - 100.00%）。中位生存期为 56.3 个月。12、24和36个月的疾病生存率分别为85.71%（IQR：69.21% - 100.00%）、68.57%（IQR：42.11% - 100.00%）、68.57%（IQR：42.11% - 100.00%）。眼睑肿瘤的主要副作用是眩晕和眼睑异常，OSSN的主要副作用是干眼症状：结论：术后 HDR-IRT 对晚期眼睑癌的控制有效。结论：术后 HDR-IRT 能有效控制晚期眼睑癌，但要有效治疗晚期 OSSN，尤其是结膜黑色素瘤，似乎更具挑战性。需要进行多中心研究，以获得更多的患者样本，并评估不同组织学和T型肿瘤的不同放疗剂量。

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引用次数: 0

NEK2 promotes colorectal cancer progression by activating the TGF-β/Smad2 signaling pathway NEK2 通过激活 TGF-β/Smad2 信号通路促进结直肠癌进展

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2024-11-04 DOI: 10.1016/j.tranon.2024.102186

Hai Qin , Manqin Yuan , Yaqin Yuan , Fengqiong Xia , Yonghong Yang

Colorectal cancer (CRC) is a prevalent malignancy with poor patient survival, and NIMA-associated kinase 2 (NEK2) has been implicated in the pathogenesis and progression of various cancers, including CRC. This study aimed to investigate the impact of NEK2 on CRC cell functionality and its interaction with the TGF-β/Smad signaling pathway. NEK2 expression in CRC tissues and cell lines was assessed, and its association with patient survival was analyzed. Functional assays, including NEK2 knockdown via lentiviral infection, RT-qPCR, Western blotting, CCK-8 assay, Transwell migration, invasion assays, and goblet cell formation assays, were employed to evaluate NEK2′s effects on CRC cell proliferation, migration, invasion, and stemness. Mechanistic studies explored the TGF-β/Smad2 signaling pathway, utilizing co-immunoprecipitation (Co-IP) and protein interaction analyses. In vivo experiments further evaluated NEK2′s role in tumor initiation, metastasis, and chemoresistance. NEK2 was found to be upregulated in CRC tissues and correlated with poor survival. NEK2 knockdown inhibited CRC cell behaviors, while NEK2 activated the TGF-β/Smad2 signaling pathway through Smad2/3 phosphorylation. Overexpression of Smad2/3 reversed NEK2 knockdown effects, confirming the importance of this pathway in CRC. In vivo, NEK2 promoted tumor initiation, metastasis, and chemoresistance, effects partially reversed by Smad2/3 overexpression. These findings reveal the critical role of NEK2 in CRC progression and underscore its potential as a therapeutic target, offering new insights into the molecular mechanisms driving CRC and informing targeted therapy development.

结肠直肠癌（CRC）是一种发病率高、患者生存率低的恶性肿瘤，而NIMA相关激酶2（NEK2）与包括CRC在内的多种癌症的发病机制和进展有关。本研究旨在探讨NEK2对CRC细胞功能的影响及其与TGF-β/Smad信号通路的相互作用。研究评估了 NEK2 在 CRC 组织和细胞系中的表达，并分析了其与患者生存的关系。通过慢病毒感染敲除 NEK2、RT-qPCR、Western 印迹、CCK-8 试验、Transwell 迁移、侵袭试验和上睑细胞形成试验等功能试验，评估了 NEK2 对 CRC 细胞增殖、迁移、侵袭和干性的影响。机理研究利用共免疫沉淀（Co-IP）和蛋白质相互作用分析探索了 TGF-β/Smad2 信号通路。体内实验进一步评估了 NEK2 在肿瘤发生、转移和化疗抵抗中的作用。研究发现，NEK2在CRC组织中上调，并与生存率低相关。敲除 NEK2 可抑制 CRC 细胞的行为，而 NEK2 可通过 Smad2/3 磷酸化激活 TGF-β/Smad2 信号通路。Smad2/3的过表达逆转了NEK2的敲除效应，证实了该通路在CRC中的重要性。在体内，NEK2促进了肿瘤的发生、转移和化疗抵抗，而Smad2/3的过表达可部分逆转这种效应。这些发现揭示了 NEK2 在 CRC 进展过程中的关键作用，并强调了其作为治疗靶点的潜力，为研究驱动 CRC 的分子机制提供了新的视角，并为靶向疗法的开发提供了信息。

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引用次数: 0

Comparative analysis of Ki-67 labeling index morphometry using deep learning, conventional image analysis, and manual counting 利用深度学习、传统图像分析和人工计数对 Ki-67 标记指数形态学进行比较分析。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2024-11-02 DOI: 10.1016/j.tranon.2024.102159

Mohammad Rizwan Alam , Kyung Jin Seo , Kwangil Yim , Phoebe Liang , Joe Yeh , Chifu Chang , Yosep Chong

The Ki-67 labeling index is essential for predicting the prognosis of breast cancer and for diagnosing neuroendocrine and gastrointestinal stromal tumors. However, current manual counting and digital image analysis (DIA)-based methods are limited in terms of accurate estimation. This study aimed to assess and compare the capabilities of different DIA systems for Ki-67 counting using the conventional manual counting method. A total of 239 tissue microarray cores from patients with stomach cancer were immunohistochemically stained for Ki-67 and digitally scanned. For the analysis, we employed three different annotation methods: whole TMA core, box selection of the epithelium, and hand-free selection of the epithelium. We used DIA system of 3DHistech, Roche, aetherAI, and manual counting by the pathologists. The annotation methods showed different Ki-67 positivity but were lower than the pathologist manual counting. The results demonstrate that the Roche system is the preferred method for analyzing the entire TMA, whereas aetherAI outperforms the box selection method. Furthermore, 3DHistech is the most accurate method for hands-free selection of the epithelium. The manual counting results showed good agreement among pathologists, with an average intraclass correlation coefficient of 0.93. These results emphasize the importance of carefully selecting annotation methods to determine Ki-67 positivity. To determine the most suitable method for individual laboratories, multiple approaches should be assessed before implementing a DIA system in routine practice.

Ki-67标记指数对于预测乳腺癌的预后以及诊断神经内分泌肿瘤和胃肠道间质瘤至关重要。然而，目前基于人工计数和数字图像分析（DIA）的方法在准确估计方面存在局限性。本研究旨在评估和比较不同 DIA 系统使用传统人工计数法进行 Ki-67 计数的能力。我们对胃癌患者的 239 个组织微阵列核芯进行了 Ki-67 免疫组化染色和数字扫描。在分析中，我们采用了三种不同的标注方法：整个 TMA 核心、上皮细胞的框选和上皮细胞的免手动选择。我们使用了罗氏公司的 3DHistech DIA 系统、etherAI 以及病理学家的手动计数。这些注释方法显示了不同的Ki-67阳性率，但均低于病理学家的人工计数。结果表明，罗氏系统是分析整个 TMA 的首选方法，而 aetherAI 则优于方框选择法。此外，3DHistech 是免手选择上皮细胞的最准确方法。病理学家之间的手动计数结果显示出良好的一致性，平均类内相关系数为 0.93。这些结果强调了谨慎选择标注方法以确定 Ki-67 阳性的重要性。为了确定最适合各个实验室的方法，在常规实践中使用 DIA 系统之前，应该对多种方法进行评估。

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引用次数: 0

Adaptive radiation strategy with V20 limitation associates with survival benefit and lower incidence of symptomatic radiation pneumonitis in stage III NSCLC patients receiving concurrent immunotherapy and thoracic radiation 在同时接受免疫疗法和胸部放射治疗的III期NSCLC患者中，限制V20的适应性放射策略不仅有利于患者生存，还能降低症状性放射性肺炎的发生率。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2024-11-02 DOI: 10.1016/j.tranon.2024.102184

Zewen Song , Xi Zhang , Yechen Ma, Shuyun Ma, Ziyang Feng, Xuewen Liu

Objectives: To evaluate the efficacy and the incidence of symptomatic radiation pneumonitis (RP) of the adaptive radiation strategy with V20 limitation in stage III non-small cell lung cancer (NSCLC) patients receiving concurrent immunotherapy and radiotherapy

Materials and Methods: We retrospectively reviewed stage III NSCLC patients received thoracic radiation with or without immunotherapy from January 2015 to September 2024 in the Third Xiangya Hospital. The overall survival (OS), progression free survival (PFS), objective response rate (ORR), and the incidence of symptomatic RP were compared among patients stratified by the sequential of immunotherapy and radiotherapy.

Results: 45 patients received concurrent immunotherapy and radiotherapy with application of the adaptive radiation strategy (the CIR group). 32 patients received simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT), 26 patients received 2 to 4 cycles neoadjuvant immuno-chemotherapy before the concurrent immunotherapy and radiotherapy, 7 patients received thoracic radiotherapy with a prescribed dosage of 50 Gy, and 10 patients received radiotherapy with CTV omission. 86.67 % (39/45) patients had a V20 ≤ 20 %. The ORR was 86.67 %. The median PFS of these patients was significantly longer than those received concurrent chemo-radiotherapy followed by immunotherapy (the PACIFIC paradigm, HR, 2.40; 95 % CI, 1.15 to 5.02; log-rank p = 0.013; median, 28.6 vs. 16.1 months p = 0.013). The median OS was not reached. 13.3 % patients in the CIR group experienced grade ≥ 2 RP and the incidence was significantly lower than that of patients received radiotherapy without immunotherapy or concurrent chemo-radiotherapy with immunotherapy consolidation.

Conclusions: The application of adaptive radiotherapy strategies with V20 limitation demonstrated robust antitumor activity and reduced pulmonary toxicity in stage III NSCLC patients receiving concurrent ICIs treatment and thoracic radiation. This treatment modality deserves further validation as a promising therapy in patients with treatment-naive, unresectable, stage III NSCLC.

目的评估同时接受免疫治疗和放疗的III期非小细胞肺癌（NSCLC）患者采用V20限制的自适应放射策略的疗效和症状性放射性肺炎（RP）的发生率材料与方法：我们回顾性研究了2015年1月至2024年9月在湘雅三医院接受胸部放射治疗或未接受免疫治疗的III期NSCLC患者。结果：45名患者同时接受了免疫治疗和放疗：45名患者同时接受了免疫疗法和放疗，并应用了自适应放射策略（CIR组）。32名患者接受了同步综合增强调强放疗（SIB-IMRT），26名患者在同步免疫治疗和放疗前接受了2至4个周期的新辅助免疫化疗，7名患者接受了规定剂量为50 Gy的胸部放疗，10名患者接受了省略CTV的放疗。86.67%（39/45）的患者 V20 ≤ 20%。ORR为86.67%。这些患者的中位生存期明显长于同时接受放化疗和免疫治疗的患者（PACIFIC 范例，HR，2.40；95 % CI，1.15 至 5.02；log-rank p = 0.013；中位 28.6 个月 vs. 16.1 个月 p = 0.013）。未达到中位生存期。CIR组13.3%的患者出现≥2级RP，其发生率明显低于未接受免疫治疗的放疗患者或同时接受免疫治疗巩固化疗-放疗的患者：结论：在同时接受 ICIs 治疗和胸部放疗的 III 期 NSCLC 患者中，应用限制 V20 的适应性放疗策略显示出强大的抗肿瘤活性，并降低了肺毒性。这种治疗模式作为一种有前景的疗法，值得在未接受治疗、无法切除的III期NSCLC患者中进一步验证。

{"title":"Adaptive radiation strategy with V20 limitation associates with survival benefit and lower incidence of symptomatic radiation pneumonitis in stage III NSCLC patients receiving concurrent immunotherapy and thoracic radiation","authors":"Zewen Song , Xi Zhang , Yechen Ma, Shuyun Ma, Ziyang Feng, Xuewen Liu","doi":"10.1016/j.tranon.2024.102184","DOIUrl":"10.1016/j.tranon.2024.102184","url":null,"abstract":"<div><div>Objectives: To evaluate the efficacy and the incidence of symptomatic radiation pneumonitis (RP) of the adaptive radiation strategy with V20 limitation in stage III non-small cell lung cancer (NSCLC) patients receiving concurrent immunotherapy and radiotherapy</div><div>Materials and Methods: We retrospectively reviewed stage III NSCLC patients received thoracic radiation with or without immunotherapy from January 2015 to September 2024 in the Third Xiangya Hospital. The overall survival (OS), progression free survival (PFS), objective response rate (ORR), and the incidence of symptomatic RP were compared among patients stratified by the sequential of immunotherapy and radiotherapy.</div><div>Results: 45 patients received concurrent immunotherapy and radiotherapy with application of the adaptive radiation strategy (the <em>CIR</em> group). 32 patients received simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT), 26 patients received 2 to 4 cycles neoadjuvant immuno-chemotherapy before the concurrent immunotherapy and radiotherapy, 7 patients received thoracic radiotherapy with a prescribed dosage of 50 Gy, and 10 patients received radiotherapy with CTV omission. 86.67 % (39/45) patients had a V20 ≤ 20 %. The ORR was 86.67 %. The median PFS of these patients was significantly longer than those received concurrent chemo-radiotherapy followed by immunotherapy (the PACIFIC paradigm, HR, 2.40; 95 % CI, 1.15 to 5.02; log-rank <em>p</em> = 0.013; median, 28.6 vs. 16.1 months <em>p</em> = 0.013). The median OS was not reached. 13.3 % patients in the <em>CIR</em> group experienced grade ≥ 2 RP and the incidence was significantly lower than that of patients received radiotherapy without immunotherapy or concurrent chemo-radiotherapy with immunotherapy consolidation.</div><div>Conclusions: The application of adaptive radiotherapy strategies with V20 limitation demonstrated robust antitumor activity and reduced pulmonary toxicity in stage III NSCLC patients receiving concurrent ICIs treatment and thoracic radiation. This treatment modality deserves further validation as a promising therapy in patients with treatment-naive, unresectable, stage III NSCLC.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"51 ","pages":"Article 102184"},"PeriodicalIF":5.0,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568749","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

The triad in current neuroblastoma challenges: Targeting antigens, enhancing effective cytotoxicity and accurate 3D in vitro modelling 当前神经母细胞瘤面临的三重挑战：靶向抗原、增强有效细胞毒性和精确三维体外建模。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2024-11-02 DOI: 10.1016/j.tranon.2024.102176

Ellen King , Ronja Struck , Olga Piskareva

Neuroblastoma is an embryonic tumour originating from neural crest cells and accounts for nearly 15 % of all childhood cancer deaths. Despite the implementation of intense multimodal therapy for neuroblastoma, half of the high-risk cohort will relapse with metastatic foci resistant to conventional therapies. There is an urgent need for novel precision medicine approaches to improve patient survival and ensure healthy post-treatment lives for these children.

Immunotherapy holds promise for such therapeutics; however, developing effective options has been disappointing despite decades of research. The immunosuppressive tumour-immune microenvironment presents a significant challenge amplified with low mutational burden in neuroblastoma, even with the new discovered tumour antigens. Innovative, practical, and comprehensive approaches are crucial for designing and testing immunotherapies capable of passing clinical trials. Replacing animal models with physiologically relevant in vitro systems will expedite this process and provide new insights into exploitable tumour-immune cell interactions. This review examines this three-pronged approach in neuroblastoma immunotherapy: tumour antigen discovery, immunomodulation, and 3D in vitro tumour models, and discusses current and emerging insights into these strategies to address neuroblastoma immunotherapy challenges.

神经母细胞瘤是一种起源于神经嵴细胞的胚胎肿瘤，占儿童癌症死亡总数的近15%。尽管对神经母细胞瘤实施了密集的多模式疗法，但半数高危人群仍会复发，出现对传统疗法耐药的转移灶。目前迫切需要新型精准医疗方法来提高患者的生存率，确保这些儿童在治疗后能健康地生活。免疫疗法为此类疗法带来了希望；然而，尽管进行了数十年的研究，但开发出的有效方案却令人失望。免疫抑制性肿瘤-免疫微环境是神经母细胞瘤面临的一项重大挑战，即使是新发现的肿瘤抗原，其突变负荷也很低。创新、实用和全面的方法对于设计和测试能够通过临床试验的免疫疗法至关重要。用与生理相关的体外系统取代动物模型将加快这一进程，并为利用肿瘤-免疫细胞相互作用提供新的见解。这篇综述探讨了神经母细胞瘤免疫疗法中的三管齐下方法：肿瘤抗原发现、免疫调节和三维体外肿瘤模型，并讨论了这些策略在应对神经母细胞瘤免疫疗法挑战方面的现有见解和新见解。

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引用次数: 0

ISO-upregulated BECN1 specifically promotes LC3B-dependent autophagy and anticancer activity in invasive bladder cancer ISO上调的BECN1能特异性地促进浸润性膀胱癌中依赖LC3B的自噬和抗癌活性。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2024-11-02 DOI: 10.1016/j.tranon.2024.102178

Xiaohui Hua , Daimin Xiang , Jiheng Xu , Shouyue Zhang , Shuai Wu , Zhongxian Tian , Junlan Zhu , Chuanshu Huang

Isorhapontigenin (ISO), an active compound isolated from the Chinese herb Gnetum Cleistostachyum, exhibited strong preventive and therapeutic effects on bladder cancer (BC) both in vitro and in vivo. Our previous studies revealed that ISO-induced autophagy is crucial for its anti-cancer activity. However, the underlying mechanism remains unclear. Here, we showed that BECN1, an important autophagic protein, was induced by ISO treatment and played crucial roles in ISO-induced late phase of LC3B-dependent, and LC3A-independent autophagy, as well as anti-cancer activity. Downregulation of BECN1 was observed in human BCs and BBN-induced mouse invasive BC tissues, whereas co-treatment with ISO completely reversed BECN1 downregulation in BBN-induced mouse invasive BCs. Consistently, ISO treatment significantly increased BECN1 expression in vitro in a dose- and time-dependent manner. Depletion of BECN1 significantly impaired LC3B-dependent autophagy following ISO treatment, as well as abolished the inhibitory effect of ISO on anchorage-independent growth of human BC cells. Mechanistic studies revealed that BECN1 induction was mediated by ISO downregulation of c-Myc, which resulted in miR-613 reduction, in turn leading to increased NCL translation and further promoting NCL binding to BECN1 mRNA, subsequently stabilizing BECN1 mRNA. In conclusion, our results demonstrate that by activating c-Myc/miR-613/NCL axis, ISO treatment results in BECN1 posttranscriptional upregulation, which specifically initiates LC3B-dependent autophagy and anti-cancer activity. Our findings further strengths our application of ISO for therapy of high-grade invasive BC (HGIBC) patients.

从中草药钩藤中分离出来的活性化合物异钩藤甙元（ISO）在体外和体内对膀胱癌（BC）都有很强的预防和治疗作用。我们之前的研究发现，ISO诱导的自噬是其抗癌活性的关键。然而，其潜在机制仍不清楚。在这里，我们发现 ISO 会诱导一种重要的自噬蛋白 BECN1，它在 ISO 诱导的 LC3B 依赖性自噬和 LC3A 非依赖性自噬晚期阶段以及抗癌活性中起着关键作用。在人类BCs和BBN诱导的小鼠浸润性BC组织中观察到了BECN1的下调，而在BBN诱导的小鼠浸润性BCs中，与ISO联合处理可完全逆转BECN1的下调。同样，ISO 处理能以剂量和时间依赖性的方式显著增加 BECN1 在体外的表达。ISO处理后，BECN1的缺失会明显影响LC3B依赖性自噬，并消除ISO对人BC细胞锚定依赖性生长的抑制作用。机理研究发现，BECN1诱导是通过ISO下调c-Myc，导致miR-613减少，进而导致NCL翻译增加，进一步促进NCL与BECN1 mRNA结合，继而稳定BECN1 mRNA。总之，我们的研究结果表明，通过激活 c-Myc/miR-613/NCL 轴，ISO 处理可导致 BECN1 转录后上调，从而特异性地启动 LC3B 依赖性自噬和抗癌活性。我们的发现进一步加强了 ISO 在治疗高级别浸润性 BC（HGIBC）患者中的应用。

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引用次数: 0

Cryoablation synergizes with anti-PD-1 immunotherapy induces an effective abscopal effect in murine model of cervical cancer 在宫颈癌小鼠模型中，冷冻消融与抗PD-1免疫疗法协同诱导有效的脱落效应。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2024-11-02 DOI: 10.1016/j.tranon.2024.102175

Xiaoming Yang , Xiaoyan Gao , Chen Xu , Ting Ni , Yaru Sheng , Jing Wang , Xiao Sun , Jiangjing Yuan , Lin Zhang , Yudong Wang

Background

Immune checkpoint inhibitors (ICIs), especially anti-PD-1/PD-L1 antibodies, have emerged as promising therapeutic options for cervical cancer. However, the efficacy of anti-PD-1 antibody monotherapy is limited. Cryoablation could elicit an anti-tumor immune response, thereby presenting itself as a potential approach to augment the response of ICIs. The aim of our study was to investigate the systemic immunological effects of cryoablation and the potential synergistic anti-tumor effects of cryoablation and anti-PD-1 antibody in cervical cancer.

Methods

We established U14 murine bilateral subcutaneous cervical cancer model, wherein the primary tumors were treated with cryoablation. Flow cytometry, immunohistochemistry and RNA-seq were used to analyze the immune cell infiltration and immune-associated pathways in the secondary tumor.

Results

Our study revealed that cryoablation reprogrammed the immune landscape, leading to an enhanced infiltration of CD8⁺ T cell in distant tumors. Cryoablation created a conducive environment for increasing the efficacy of anti-PD-1 immunotherapy. Cryoablation in combination with anti-PD-1 antibody inhibited distant tumors growth and improved mouse survival. Mechanistically, this combination therapy could augment the infiltration of CD8⁺ T cells, CD4⁺ T cells, dendritic cells and M1-like tumor-associated macrophages, enhance multiple aspects of antitumor immune response, and reduce immunosuppressive cells such as M2-like tumor-associated macrophages and myeloid-derived suppressor cells in distant tumors.

Conclusions

Combination therapy with cryoablation and anti-PD-1 antibody induces an effective abscopal effect in murine model of cervical cancer and may be a novel therapeutic approach for patients with advanced/recurrent cervical cancer.

背景：免疫检查点抑制剂（ICIs），尤其是抗PD-1/PD-L1抗体，已成为治疗宫颈癌的有前途的选择。然而，抗PD-1抗体单一疗法的疗效有限。低温消融可引起抗肿瘤免疫反应，从而成为增强 ICIs 反应的潜在方法。我们的研究旨在探讨冷冻消融的全身免疫学效应以及冷冻消融和抗PD-1抗体在宫颈癌中的潜在协同抗肿瘤效应：方法：我们建立了U14小鼠双侧皮下宫颈癌模型，对原发肿瘤进行冷冻消融治疗。方法：我们建立了 U14 小鼠双侧皮下宫颈癌模型，对原发肿瘤进行冷冻消融治疗，并使用流式细胞术、免疫组化和 RNA-seq 分析继发肿瘤中的免疫细胞浸润和免疫相关通路：我们的研究发现，冷冻消融重塑了免疫格局，导致远处肿瘤中 CD8+ T 细胞浸润增强。低温消融为提高抗PD-1免疫疗法的疗效创造了有利环境。低温消融联合抗PD-1抗体可抑制远处肿瘤的生长，提高小鼠的存活率。从机理上讲，这种联合疗法可以增加CD8+ T细胞、CD4+ T细胞、树突状细胞和M1样肿瘤相关巨噬细胞的浸润，增强多方面的抗肿瘤免疫反应，减少远处肿瘤中的免疫抑制细胞，如M2样肿瘤相关巨噬细胞和髓源性抑制细胞：在宫颈癌小鼠模型中，冷冻消融与抗PD-1抗体的联合治疗可诱导有效的脱落效应，可能是晚期/复发性宫颈癌患者的一种新型治疗方法。

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引用次数: 0

Prostate-specific antigen, digital rectal examination, and prostate cancer detection: A study based on more than 7000 transrectal ultrasound-guided prostate biopsies in Ghana 前列腺特异性抗原、数字直肠检查和前列腺癌检测：基于加纳 7000 多例经直肠超声引导前列腺活检的研究。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2024-11-02 DOI: 10.1016/j.tranon.2024.102163

James Edward Mensah , Evans Akpakli , Mathew Kyei , Kenneth Klufio , Isaac Asiedu , Kweku Asante , Bernard Toboh , Micheal Darko Ashaley , Ben Molai Addo , Bernard Morton , Erica Akoto Quist

Purpose of the study

This study aims to determine the role of serum prostate-specific antigen (PSA) levels and digital rectal examination (DRE) in predicting the histological outcomes of prostate biopsies by analyzing a database of over 7000 patients who underwent transrectal ultrasound (TRUS)-guided prostate biopsies.

Methods

We conducted a retrospective analysis of men who underwent TRUS-guided prostate biopsies at Korle Bu Teaching Hospital, a tertiary referral center in Accra, Ghana, from July 2005 to December 2022. The biopsies, which included 10 to 12 core samples, were prompted by PSA levels greater than 4.0 ng/mL, abnormal DRE findings, or both. We then correlated histopathology results with PSA and DRE findings.

Results

Out of 7,338 patients who presented for biopsy, 76.3% were between the ages of 60 and 79. Histology reports were available for 5,289 patients, of whom 2,564 (48.5%) were diagnosed with prostate cancer. Cancer detection rates based on PSA levels were as follows: 21.6% for PSA <4 ng/mL, 21.7% for PSA 4-10 ng/mL, 32.7% for PSA 10-20 ng/mL, 53.0% for PSA 20-50 ng/mL, 71.5% for PSA 50-100 ng/mL, and 92.0% for PSA >100 ng/mL. When DRE findings were classified according to the 2016 TNM System (AJCC 8th Edition) as T1, T2, T3, and T4, cancer detection rates were 26.8%, 51.8%, 87.6%, and 95.7%, respectively. The overall cancer detection rate was significantly higher with abnormal DRE findings (64.6% vs. 26.7%, p < 0.001). Additionally, 78.2% of the detected cancers were high-grade (Gleason score of 7 or more).

Conclusion

This extensive study of Ghanaian men undergoing TRUS biopsies reveals a high prostate cancer detection rate, with nearly 80% of the detected cancers being high-grade. These findings underscore the importance of PSA and DRE in the early detection of prostate cancer and should be considered in patient counseling and discussions regarding the implementation of prostate cancer screening programs in this population.

研究目的本研究旨在通过分析7000多名接受经直肠超声（TRUS）引导的前列腺活检患者的数据库，确定血清前列腺特异性抗原（PSA）水平和数字直肠检查（DRE）在预测前列腺活检组织学结果方面的作用：我们对2005年7月至2022年12月期间在加纳阿克拉三级转诊中心Korle Bu教学医院接受TRUS引导下前列腺活检的男性患者进行了回顾性分析。活组织检查包括 10 到 12 个核心样本，其原因是 PSA 水平超过 4.0 纳克/毫升、DRE 结果异常或两者兼而有之。然后，我们将组织病理学结果与 PSA 和 DRE 结果进行了关联：在接受活组织检查的 7,338 名患者中，76.3% 的患者年龄在 60 至 79 岁之间。5,289 名患者获得了组织学报告，其中 2,564 人（48.5%）被确诊为前列腺癌。根据 PSA 水平得出的癌症检出率如下：PSA 100 纳克/毫升的癌症检出率为 21.6%。如果根据 2016 TNM 系统（AJCC 第 8 版）将 DRE 结果分为 T1、T2、T3 和 T4，癌症检出率分别为 26.8%、51.8%、87.6% 和 95.7%。DRE 结果异常的癌症总检出率明显更高（64.6% 对 26.7%，P < 0.001）。此外，78.2%的癌症为高级别癌症（Gleason评分为7分或以上）：这项针对接受 TRUS 活检的加纳男性的广泛研究显示，前列腺癌的检出率很高，其中近 80% 的癌症为高级别。这些发现强调了前列腺特异性抗原（PSA）和前列腺特异性抗原（DRE）在早期发现前列腺癌方面的重要性，在对患者进行咨询和讨论如何在这些人群中实施前列腺癌筛查计划时应考虑到这一点。

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引用次数: 0

Predicting overall survival in hepatocellular carcinoma patients via a combined MRI radiomics and pathomics signature 通过磁共振成像放射组学和病理组学联合特征预测肝细胞癌患者的总生存期。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2024-11-02 DOI: 10.1016/j.tranon.2024.102174

Lijuan Feng , Wanyun Huang , Xiaoyu Pan , Fengqiu Ruan , Xuan Li , Siyuan Tan , Liling Long

Objective

This study aims to develop and validate a radiopathomics model that integrates radiomic and pathomic features to predict overall survival (OS) in hepatocellular carcinoma (HCC) patients.

Materials and methods

This study involved 126 HCC patients who underwent hepatectomy and were followed for more than 5 years. Radiomic features were extracted from arterial-phase (AP) and portal venous-phase (PVP) MRI scans, whereas pathomic features were obtained from whole-slide images (WSIs) of the HCC patients. Using LASSO Cox regression, both radiomics and pathomics signatures were established. A combined radiopathomics nomogram for predicting OS was constructed and validated. The correlation between the radiopathomics nomogram and OS prediction was evaluated, demonstrating its potential clinical utility in prognosis assessment.

Results

We selected four radiomic features from the AP and PVP MRI scans to construct a signature, achieving a concordance index (C-index) of 0.739 in the training cohort and 0.724 in the validation cohort; these results indicate favourable 5-year OS prediction. Similarly, from 1,141 pathomics features extracted from WSIs, 15 were chosen for a pathomics signature, which had C-indexes of 0.821 and 0.808 in the training and validation cohorts, respectively. The most robust performance was delivered by a radiopathomics nomogram, with C-index values of 0.840 in the training cohort and 0.875 in the validation cohort. Decision curve analysis (DCA) confirmed the highest net benefit achievable by the combined radiopathomics nomogram.

Conclusion

Our findings indicate that the radiopathomics nomogram can serve as a predictive marker for hepatectomy prognosis in HCC patients and has the potential to enhance personalized therapeutic approaches.

目的：本研究旨在开发和验证一种放射病理组学模型，该模型综合了放射学和病理学特征，可预测肝细胞癌（HCC）患者的总生存率（OS）：本研究旨在开发和验证一种放射病理组学模型，该模型综合了放射组学和病理组学特征，可预测肝细胞癌（HCC）患者的总生存率（OS）：本研究涉及126名接受肝切除术并随访5年以上的HCC患者。从动脉期（AP）和门静脉期（PVP）MRI扫描中提取放射学特征，而病理学特征则从HCC患者的全滑动图像（WSI）中获得。通过 LASSO Cox 回归，建立了放射组学和病理组学特征。构建并验证了用于预测OS的综合放射病理组学提名图。评估了放射病理组学提名图与OS预测之间的相关性，证明了其在预后评估中的潜在临床实用性：我们从 AP 和 PVP MRI 扫描中选取了四个放射病理特征来构建特征，在训练队列中获得了 0.739 的一致性指数（C-index），在验证队列中获得了 0.724 的一致性指数（C-index）；这些结果表明了良好的 5 年期 OS 预测。同样，从 WSIs 中提取的 1,141 个病理组学特征中，有 15 个被选为病理组学特征，在训练队列和验证队列中的 C 指数分别为 0.821 和 0.808。放射病理组学提名图的表现最为稳健，在训练组中的C指数值为0.840，在验证组中的C指数值为0.875。决策曲线分析（DCA）证实了综合放射病理组学提名图可实现的最高净效益：我们的研究结果表明，放射病理组学提名图可以作为 HCC 患者肝切除术预后的预测标志物，并有可能增强个性化治疗方法。

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引用次数: 0