Pub Date : 2024-11-02DOI: 10.1016/j.tranon.2024.102164
Ming Xu , Chuanmin Deng , Zhongran Man , Hongyi Zhu
Background
Gallbladder cancer (GBC) is one of the most lethal malignancies worldwide with an extremely poor prognosis. Previous studies have suggested that tripartite motif containing 47 (TRIM47) is involved in the progression of numerous cancers. However, the molecular mechanism and function of TRIM47 in GBC remain unclear.
Methods
The clinical significance of TRIM47 was evaluated using immunohistochemistry. Functional assays were performed in vitro and in vivo to determine the role of TRIM47 in GBC. Mass spectrometric analysis, western blotting, and immunoprecipitation assays were performed to investigate the molecular mechanisms involved.
Results
In this study, TRIM47 was upregulated in GBC tissues and associated with shorter overall survival rates and TRIM47 was involved in GBC cell proliferation, migration, and apoptosis. Mechanistically, TRIM47 interacts with PARP1 and mediates the K63-linked polyubiquitination of PARP1, thereby stabilizing its expression. Furthermore, TRIM47 activated the AKT signaling pathway via PARP1.
Conclusion
The present study revealed that TRIM47 contributes to the progression of GBC and is therefore an important biomarker for predicting the prognosis of GBC and for therapeutic intervention.
{"title":"TRIM47 is a prognostic biomarker for gallbladder cancer and promotes tumor progression through regulating K63-linked ubiquitination of PARP1","authors":"Ming Xu , Chuanmin Deng , Zhongran Man , Hongyi Zhu","doi":"10.1016/j.tranon.2024.102164","DOIUrl":"10.1016/j.tranon.2024.102164","url":null,"abstract":"<div><h3>Background</h3><div>Gallbladder cancer (GBC) is one of the most lethal malignancies worldwide with an extremely poor prognosis. Previous studies have suggested that tripartite motif containing 47 (TRIM47) is involved in the progression of numerous cancers. However, the molecular mechanism and function of TRIM47 in GBC remain unclear.</div></div><div><h3>Methods</h3><div>The clinical significance of TRIM47 was evaluated using immunohistochemistry. Functional assays were performed <em>in vitro</em> and <em>in vivo</em> to determine the role of TRIM47 in GBC. Mass spectrometric analysis, western blotting, and immunoprecipitation assays were performed to investigate the molecular mechanisms involved.</div></div><div><h3>Results</h3><div>In this study, TRIM47 was upregulated in GBC tissues and associated with shorter overall survival rates and TRIM47 was involved in GBC cell proliferation, migration, and apoptosis. Mechanistically, TRIM47 interacts with PARP1 and mediates the K63-linked polyubiquitination of PARP1, thereby stabilizing its expression. Furthermore, TRIM47 activated the AKT signaling pathway via PARP1.</div></div><div><h3>Conclusion</h3><div>The present study revealed that TRIM47 contributes to the progression of GBC and is therefore an important biomarker for predicting the prognosis of GBC and for therapeutic intervention.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"51 ","pages":"Article 102164"},"PeriodicalIF":5.0,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569153","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}
Pub Date : 2024-11-02DOI: 10.1016/j.tranon.2024.102170
Jing Shi , Yebin Yang , Fangci Chen , Linpo Zhou , Haoran Wei , Fanhe Dong , Xiang Wang , Yuqiang Shan , Tianwei Chen
Ribosomal protein L36A (RPL36A) was one of the most upregulated proteins in colorectal cancer (CRC), yet its role in colorectal cancer (CRC) remains largely unexplored, with limited studies investigating its expression and biological functions. In this investigation, we confirmed a marked upregulation of RPL36A in CRC tissues, correlating with an adverse prognosis. Silencing RPL36A markedly attenuated CRC cell malignant properties and tumor xenograft growth. Further mechanistic analysis indicated that RPL36A depletion diminished phosphorylated ERK levels, subsequently impacting the expression of c-Myc and ELK1, key downstream effectors in the MAPK/ERK pathway. Notably, the tumor-suppressive effects of RPL36A knockdown could be negated by an ERK activator. Collectively, our findings underscore the oncogenic function of RPL36A in CRC and propose it as a potential target for therapeutic intervention.
{"title":"RPL36A activates ERK pathway and promotes colorectal cancer growth","authors":"Jing Shi , Yebin Yang , Fangci Chen , Linpo Zhou , Haoran Wei , Fanhe Dong , Xiang Wang , Yuqiang Shan , Tianwei Chen","doi":"10.1016/j.tranon.2024.102170","DOIUrl":"10.1016/j.tranon.2024.102170","url":null,"abstract":"<div><div>Ribosomal protein L36A (RPL36A) was one of the most upregulated proteins in colorectal cancer (CRC), yet its role in colorectal cancer (CRC) remains largely unexplored, with limited studies investigating its expression and biological functions. In this investigation, we confirmed a marked upregulation of RPL36A in CRC tissues, correlating with an adverse prognosis. Silencing RPL36A markedly attenuated CRC cell malignant properties and tumor xenograft growth. Further mechanistic analysis indicated that RPL36A depletion diminished phosphorylated ERK levels, subsequently impacting the expression of c-Myc and ELK1, key downstream effectors in the MAPK/ERK pathway. Notably, the tumor-suppressive effects of RPL36A knockdown could be negated by an ERK activator. Collectively, our findings underscore the oncogenic function of RPL36A in CRC and propose it as a potential target for therapeutic intervention.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"51 ","pages":"Article 102170"},"PeriodicalIF":5.0,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569146","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}
Pub Date : 2024-11-01DOI: 10.1016/j.tranon.2024.102171
Yuhan Wei , Qiao Li , Hongnan Mo , Yalong Qi , Hewei Ge , Xiaoying Sun , Ying Fan , Pin Zhang , Jiayu Wang , Yang Luo , Jing Wang , Fei Ma
Background
The selection of appropriate chemotherapy backbone agents in combination with neoadjuvant immunotherapy for triple-negative breast cancer (TNBC) remains unclear. Herein, we aimed to evaluate the efficacy and safety of anthracycline-free and anthracycline-containing regimens coupled with neoadjuvant immunotherapy.
Method
This retrospective study included 87 patients with TBNC who received neoadjuvant immunotherapy combined with various chemotherapy regimens at three research centers from November 2020 to November 2023. The primary objective was pathological complete response (pCR), while secondary objectives included overall response rates, event-free survival (EFS), and the incidence of adverse events. A subgroup analysis was performed to delineate patients who may substantially benefit from distinct therapeutic strategies.
Results
Coupled with immunotherapy, anthracycline-free regimens achieved comparable pCR rates (55.1 % vs. 51.4 %; Odds ratio, 1.16; 95 % confidence interval [CI], 0.49–2.74; p = 0.73) and EFS (Hazard ratio, 0.66; 95 % CI, 0.18–2.45; p = 0.53) to anthracycline-containing regimens. According to subgroup analyses, the tumor stage (p = 0.017) and lymph node stage (p = 0.011) exhibit contradictory predictive power for the pCR rate of anthracycline-free regimens when compared with that of anthracycline-containing regimens. Specifically, anthracycline-free regimens yielded significantly higher pCR rates in patients without lymph node metastasis than anthracycline-containing regimens (p = 0.021). Pooled analyses further confirmed the results of both total and subgroup analyses. Most adverse events were grades 1–2, and no new adverse reactions were observed.
Conclusion
Anthracycline-free neoadjuvant chemotherapy regimens could serve as an effective and safe alternative immunotherapy partner for patients with TNBC, particularly in those without lymph node metastasis.
{"title":"Comparative efficacy of anthracycline-free and anthracycline-containing neoadjuvant chemoimmunotherapy regimens for triple-negative breast cancer","authors":"Yuhan Wei , Qiao Li , Hongnan Mo , Yalong Qi , Hewei Ge , Xiaoying Sun , Ying Fan , Pin Zhang , Jiayu Wang , Yang Luo , Jing Wang , Fei Ma","doi":"10.1016/j.tranon.2024.102171","DOIUrl":"10.1016/j.tranon.2024.102171","url":null,"abstract":"<div><h3>Background</h3><div>The selection of appropriate chemotherapy backbone agents in combination with neoadjuvant immunotherapy for triple-negative breast cancer (TNBC) remains unclear. Herein, we aimed to evaluate the efficacy and safety of anthracycline-free and anthracycline-containing regimens coupled with neoadjuvant immunotherapy.</div></div><div><h3>Method</h3><div>This retrospective study included 87 patients with TBNC who received neoadjuvant immunotherapy combined with various chemotherapy regimens at three research centers from November 2020 to November 2023. The primary objective was pathological complete response (pCR), while secondary objectives included overall response rates, event-free survival (EFS), and the incidence of adverse events. A subgroup analysis was performed to delineate patients who may substantially benefit from distinct therapeutic strategies.</div></div><div><h3>Results</h3><div>Coupled with immunotherapy, anthracycline-free regimens achieved comparable pCR rates (55.1 % vs. 51.4 %; Odds ratio, 1.16; 95 % confidence interval [CI], 0.49–2.74; <em>p</em> = 0.73) and EFS (Hazard ratio, 0.66; 95 % CI, 0.18–2.45; <em>p</em> = 0.53) to anthracycline-containing regimens. According to subgroup analyses, the tumor stage (<em>p</em> = 0.017) and lymph node stage (<em>p</em> = 0.011) exhibit contradictory predictive power for the pCR rate of anthracycline-free regimens when compared with that of anthracycline-containing regimens. Specifically, anthracycline-free regimens yielded significantly higher pCR rates in patients without lymph node metastasis than anthracycline-containing regimens (<em>p</em> = 0.021). Pooled analyses further confirmed the results of both total and subgroup analyses. Most adverse events were grades 1–2, and no new adverse reactions were observed.</div></div><div><h3>Conclusion</h3><div>Anthracycline-free neoadjuvant chemotherapy regimens could serve as an effective and safe alternative immunotherapy partner for patients with TNBC, particularly in those without lymph node metastasis.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"51 ","pages":"Article 102171"},"PeriodicalIF":5.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142565251","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}
Pub Date : 2024-11-01DOI: 10.1016/j.tranon.2024.102155
Bide Liu , Xun Li , Shuheng Wang , Hongliang Jia , Xiaoan Zhang , Qiang Dong , Jiuzhi Li
The incidence of prostate cancer (PCa) is increasing annually, making it the leading cause of tumor-related mortality in males. The available treatment options for metastatic PCa are limited. Vasculogenic mimicry (VM), an emerging phenomenon involving aggressive tumor cells, has a significant impact on patient survival. Misregulation of Wnt5a expression is commonly observed during cancer progression. However, there is a lack of comprehensive studies investigating the effects of Wnt5a on tumor VM formation. In this study, we demonstrate that alterations in wnt5a expression, either through gain or loss, have a significant influence on the formation of VM in tumor cells mediated by cell stemness and EMT progression. Further research has demonstrated that Wnt5a regulates the formation of VM through the PI3K/JNK signaling pathway. These experimental findings offer a novel avenue for the clinical management of prostate cancer.
前列腺癌（PCa）的发病率逐年上升，已成为男性肿瘤相关死亡的主要原因。转移性前列腺癌的现有治疗方案十分有限。血管生成模拟（VM）是一种涉及侵袭性肿瘤细胞的新兴现象，对患者的生存有重大影响。在癌症进展过程中，通常会观察到 Wnt5a 表达的失调。然而，目前还缺乏有关 Wnt5a 对肿瘤 VM 形成影响的全面研究。在这项研究中，我们证明了 Wnt5a 表达的改变，无论是增益还是缺失，都会对肿瘤细胞中由细胞干性和 EMT 进展介导的 VM 的形成产生重大影响。进一步的研究表明，Wnt5a 通过 PI3K/JNK 信号通路调控 VM 的形成。这些实验发现为前列腺癌的临床治疗提供了一条新途径。
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Pub Date : 2024-10-28DOI: 10.1016/j.tranon.2024.102162
Antonio Macciò , Clelia Madeddu
In a recent article titled "Embracing Cancer Complexity: Hallmarks of Systemic Disease" published in Cell, Swaton et al. propose the idea of cancer as a guest that develops within a host. They discuss the possible causes and events of neoplastic cell dysregulations within an organism, highlighting events such as cachexia and thrombosis. However, we believe that to understand cancer-associated phenomena better, cancer cannot be considered a guest. In reality, cancer is born, develops, and spreads within its environment. It does not come from outside but instead uses the same system in which it lives to promote its death plan. Indeed, today we know that cancer not only causes local symptoms in the affected organ but also leads to systemic symptoms, which are evidence of inflammation associated with cancer. Inflammation is vital in controlling oncogenesis and neoplastic proliferation during the resistance phase, which is a critical moment for the immune system to demonstrate its effectiveness. However, if the immune system causes immunopathological damage, it may lead to necrosis and eventually to the tolerance phase, which can result in systemic symptoms. Understanding these phenomena thoroughly explains thrombophilia, anemia, sarcopenia, and iron metabolism disruption in advanced-stage neoplastic patients. The concept of the microenvironment takes on a different meaning in this context. The same cells that should oppose cancer in the tolerance phase now participate in a process that self-maintains, favoring the growth of the cancer and its death plan. The exact knowledge of these mechanisms is a more modern translational approach to treating cancer and its related symptoms.
Swaton 等人最近在《细胞》（Cell）杂志上发表了一篇题为 "拥抱癌症的复杂性：系统疾病的标志"（Embracing Cancer Complexity: Hallmarks of Systemic Disease）的文章，提出了癌症是宿主体内发展的客人这一观点。他们讨论了机体内肿瘤细胞失调的可能原因和事件，并强调了恶病质和血栓形成等事件。然而，我们认为，要更好地理解与癌症相关的现象，就不能将癌症视为客人。实际上，癌症是在环境中诞生、发展和扩散的。它并非来自外部，而是利用其生存的同一系统来推动其死亡计划。事实上，今天我们知道，癌症不仅会在受影响的器官中引起局部症状，还会导致全身症状，这就是与癌症相关的炎症的证据。炎症对于控制抗药性阶段的肿瘤发生和肿瘤增殖至关重要，而抗药性阶段正是免疫系统展示其有效性的关键时刻。但是，如果免疫系统造成免疫病理损伤，则可能导致坏死，最终进入耐受期，从而引发全身症状。了解了这些现象，就能彻底解释晚期肿瘤患者的血栓性疾病、贫血、肌少症和铁代谢紊乱。在这种情况下，微环境的概念就有了不同的含义。在耐受阶段本应与癌症对抗的细胞，现在却参与了一个自我维持的过程，有利于癌症的生长及其死亡计划。准确了解这些机制是治疗癌症及其相关症状的一种更现代的转化方法。
{"title":"Cancer is not a guest","authors":"Antonio Macciò , Clelia Madeddu","doi":"10.1016/j.tranon.2024.102162","DOIUrl":"10.1016/j.tranon.2024.102162","url":null,"abstract":"<div><div>In a recent article titled \"Embracing Cancer Complexity: Hallmarks of Systemic Disease\" published in Cell, Swaton et al. propose the idea of cancer as a guest that develops within a host. They discuss the possible causes and events of neoplastic cell dysregulations within an organism, highlighting events such as cachexia and thrombosis. However, we believe that to understand cancer-associated phenomena better, cancer cannot be considered a guest. In reality, cancer is born, develops, and spreads within its environment. It does not come from outside but instead uses the same system in which it lives to promote its death plan. Indeed, today we know that cancer not only causes local symptoms in the affected organ but also leads to systemic symptoms, which are evidence of inflammation associated with cancer. Inflammation is vital in controlling oncogenesis and neoplastic proliferation during the resistance phase, which is a critical moment for the immune system to demonstrate its effectiveness. However, if the immune system causes immunopathological damage, it may lead to necrosis and eventually to the tolerance phase, which can result in systemic symptoms. Understanding these phenomena thoroughly explains thrombophilia, anemia, sarcopenia, and iron metabolism disruption in advanced-stage neoplastic patients. The concept of the microenvironment takes on a different meaning in this context. The same cells that should oppose cancer in the tolerance phase now participate in a process that self-maintains, favoring the growth of the cancer and its death plan. The exact knowledge of these mechanisms is a more modern translational approach to treating cancer and its related symptoms.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"51 ","pages":"Article 102162"},"PeriodicalIF":5.0,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142530616","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}
Pub Date : 2024-10-15DOI: 10.1016/j.tranon.2024.102147
Ziyu Wu , Yifan Wang , Xin Jin , Luqiao Wang
Chimeric Antigen Receptor (CAR) T cell therapy has gained success in adoptive cell therapy for hematological malignancies. Although most CAR cell therapies in clinical trials or markets remain autologous, their acceptance has been limited due to issues like lengthy manufacturing, poor cell quality, and demanding cost. Consequently, “Off-the-shelf”, universal CAR (UCAR) cell therapy has emerged. Current concerns with UCAR therapies revolve around side effects such as graft versus host disease (GVHD) and host versus graft response (HVGR). Preclinical research on UCAR cell therapies aims to enhance efficacy and minimize these side effects. Common approaches involve gene editing techniques to knock out T cell receptor (TCR), human leukocyte antigen (HLA), and CD52 expression to mitigate GVHD and HVGR risks. However, these methods carry drawbacks including potential genotoxicity of the edited cells. Most recently, novel editing techniques, such as epigenetic editing and RNA writer systems, have been developed to reduce the risk of GVHD and HVGR, allowing for multiplex editing at different sites. Additionally, incorporating more cell types into UCAR cell therapies, like T-cell subtypes (DNT, γδT, virus-specific T cells) and NK cells, can efficiently target tumors without triggering side effects. In addition, the limited efficacy of T cells and NK cells against solid tumors is being addressed through CAR-Macrophages. In summary, CAR cell therapy has evolved to accommodate multiple cell types while expanding applications to various diseases, including hematologic malignancies and solid tumors, which holds tremendous growth potential and is promised to improve the lives of more patients in the future.
嵌合抗原受体（CAR）T 细胞疗法在血液恶性肿瘤的采用性细胞疗法中取得了成功。尽管临床试验或市场上的大多数 CAR 细胞疗法仍然是自体细胞疗法，但由于制造时间长、细胞质量差和成本高昂等问题，它们的接受程度受到了限制。因此，"现成的 "通用 CAR（UCAR）细胞疗法应运而生。目前对 UCAR 疗法的担忧主要集中在副作用上，如移植物抗宿主疾病（GVHD）和宿主抗移植物反应（HVGR）。有关 UCAR 细胞疗法的临床前研究旨在提高疗效并尽量减少这些副作用。常见的方法包括基因编辑技术，以敲除 T 细胞受体 (TCR)、人类白细胞抗原 (HLA) 和 CD52 的表达，从而降低 GVHD 和 HVGR 风险。然而，这些方法都存在缺陷，包括编辑细胞的潜在遗传毒性。最近，人们开发了新型编辑技术，如表观遗传编辑和 RNA 写入系统，以降低 GVHD 和 HVGR 风险，并可在不同部位进行多重编辑。此外，在 UCAR 细胞疗法中加入更多细胞类型，如 T 细胞亚型（DNT、γδT、病毒特异性 T 细胞）和 NK 细胞，可有效靶向肿瘤，且不会引发副作用。此外，T 细胞和 NK 细胞对实体瘤的疗效有限，这一问题正在通过 CAR 巨噬细胞得到解决。总之，CAR 细胞疗法已发展到可容纳多种细胞类型，同时将应用范围扩大到包括血液恶性肿瘤和实体瘤在内的各种疾病，具有巨大的发展潜力，有望在未来改善更多患者的生活。
{"title":"Universal CAR cell therapy: Challenges and expanding applications","authors":"Ziyu Wu , Yifan Wang , Xin Jin , Luqiao Wang","doi":"10.1016/j.tranon.2024.102147","DOIUrl":"10.1016/j.tranon.2024.102147","url":null,"abstract":"<div><div>Chimeric Antigen Receptor (CAR) T cell therapy has gained success in adoptive cell therapy for hematological malignancies. Although most CAR cell therapies in clinical trials or markets remain autologous, their acceptance has been limited due to issues like lengthy manufacturing, poor cell quality, and demanding cost. Consequently, “Off-the-shelf”, universal CAR (UCAR) cell therapy has emerged. Current concerns with UCAR therapies revolve around side effects such as graft versus host disease (GVHD) and host versus graft response (HVGR). Preclinical research on UCAR cell therapies aims to enhance efficacy and minimize these side effects. Common approaches involve gene editing techniques to knock out T cell receptor (TCR), human leukocyte antigen (HLA), and CD52 expression to mitigate GVHD and HVGR risks. However, these methods carry drawbacks including potential genotoxicity of the edited cells. Most recently, novel editing techniques, such as epigenetic editing and RNA writer systems, have been developed to reduce the risk of GVHD and HVGR, allowing for multiplex editing at different sites. Additionally, incorporating more cell types into UCAR cell therapies, like T-cell subtypes (DNT, γδT, virus-specific T cells) and NK cells, can efficiently target tumors without triggering side effects. In addition, the limited efficacy of T cells and NK cells against solid tumors is being addressed through CAR-Macrophages. In summary, CAR cell therapy has evolved to accommodate multiple cell types while expanding applications to various diseases, including hematologic malignancies and solid tumors, which holds tremendous growth potential and is promised to improve the lives of more patients in the future.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"51 ","pages":"Article 102147"},"PeriodicalIF":5.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142432753","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}
Pub Date : 2024-10-15DOI: 10.1016/j.tranon.2024.102153
Katharina Sinn , Ahmed Elbeialy , Berta Mosleh , Clemens Aigner , Karin Schelch , Viktoria Laszlo , Balazs Dome , Mir Alireza Hoda , Michael Grusch
Objectives
Lung squamous cell carcinoma (LUSC) is associated with a poor prognosis and a lack of specific treatment options. The dysregulation of activin A (ActA) has been reported in various malignancies. Herein, we investigated the diagnostic and prognostic significance of ActA in LUSC.
Materials and methods
ActA concentrations were measured using ELISA in plasma samples of 128 LUSC patients (stage I-IV) and 73 controls, and correlated those values with clinicopathological parameters and survival.
Results
ActA plasma levels were significantly higher in therapy-naive LUSC patients compared to controls (444.1 310.9 pg/mL vs 338.9 145.5 pg/mL, p = 0.010). ActA levels significantly correlated with advanced stage as well as with T and N factors. High circulating ActA levels were significantly increased in metastatic disease patients compared to M0 disease. Further, patients with ActA levels above a computationally established optimal cut-off value of 443.0 pg/mL had a significantly worse median overall (OS, 17.63 vs 64.77 months, HR 0.391, 95 % CI 0.200–0.762, p < 0.001) and median disease-/progression-free survival (DFS/PFS; 11.57 vs 30.20 months, HR 0.502, 95 % CI 0.248–1.019, p = 0.020). Multivariate analysis revealed that high ActA levels were an independent prognostic factor for shorter OS (p = 0.001) and DFS/PFS (p = 0.018). A newly developed score combining CRP and ActA levels was also an independent prognostic factor for OS and DFS/PFS.
Conclusion
Measurement of circulating ActA levels may help identify advanced-stage LUSC patients, and this value could serve as a prognostic parameter in LUSC. Thus, ActA may be a novel blood-based biomarker for identifying LUSC patients with distant metastasis.
{"title":"High circulating activin A plasma levels are associated with tumour stage and poor survival in treatment-naive lung squamous cell cancer patients","authors":"Katharina Sinn , Ahmed Elbeialy , Berta Mosleh , Clemens Aigner , Karin Schelch , Viktoria Laszlo , Balazs Dome , Mir Alireza Hoda , Michael Grusch","doi":"10.1016/j.tranon.2024.102153","DOIUrl":"10.1016/j.tranon.2024.102153","url":null,"abstract":"<div><h3>Objectives</h3><div>Lung squamous cell carcinoma (LUSC) is associated with a poor prognosis and a lack of specific treatment options. The dysregulation of activin A (ActA) has been reported in various malignancies. Herein, we investigated the diagnostic and prognostic significance of ActA in LUSC.</div></div><div><h3>Materials and methods</h3><div>ActA concentrations were measured using ELISA in plasma samples of 128 LUSC patients (stage I-IV) and 73 controls, and correlated those values with clinicopathological parameters and survival.</div></div><div><h3>Results</h3><div>ActA plasma levels were significantly higher in therapy-naive LUSC patients compared to controls (444.1 <span><math><mo>±</mo></math></span> 310.9 pg/mL vs 338.9 <span><math><mo>±</mo></math></span> 145.5 pg/mL, <em>p</em> = 0.010). ActA levels significantly correlated with advanced stage as well as with T and N factors. High circulating ActA levels were significantly increased in metastatic disease patients compared to M0 disease. Further, patients with ActA levels above a computationally established optimal cut-off value of 443.0 pg/mL had a significantly worse median overall (OS, 17.63 vs 64.77 months, HR 0.391, 95 % CI 0.200–0.762, <em>p</em> < 0.001) and median disease-/progression-free survival (DFS/PFS; 11.57 vs 30.20 months, HR 0.502, 95 % CI 0.248–1.019, <em>p</em> = 0.020). Multivariate analysis revealed that high ActA levels were an independent prognostic factor for shorter OS (<em>p</em> = 0.001) and DFS/PFS (<em>p</em> = 0.018). A newly developed score combining CRP and ActA levels was also an independent prognostic factor for OS and DFS/PFS.</div></div><div><h3>Conclusion</h3><div>Measurement of circulating ActA levels may help identify advanced-stage LUSC patients, and this value could serve as a prognostic parameter in LUSC. Thus, ActA may be a novel blood-based biomarker for identifying LUSC patients with distant metastasis.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"51 ","pages":"Article 102153"},"PeriodicalIF":5.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142433328","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}
Pub Date : 2024-10-13DOI: 10.1016/j.tranon.2024.102152
SM Bollard , J Howard , C Casalou , BS Kelly , K O'Donnell , G Fenn , J O'Reilly , R Milling , M Shields , M Wilson , A Ajaykumar , K Triana , K Wynne , DJ Tobin , PA Kelly , A McCann , SM Potter
Background
Plasma-derived Extracellular Vesicles (EVs) have been suggested as novel biomarkers in melanoma, due to their ability to reflect the cell of origin and ease of collection. This study aimed to identify novel EV biomarkers that can discriminate between disease stages. This was achieved by characterising the plasma-derived EVs of patients with melanoma, and comparing their proteomic and metabolomic profile to those from healthy controls.
Methods
EVs were isolated from the plasma of 36 patients with melanoma and 13 healthy controls using Size Exclusion Chromatography. Proteomic and Metabolomic Analyses were performed, and machine learning algorithms were used to identify potential proteins and metabolites to differentiate the plasma-derived EVs from melanoma patients of different disease stages.
Results
The concentration and size of the EV population isolated was similar between groups. Proteins (APOC4, PRG4, PLG, TNC, VWF and SERPIND1) and metabolites (lyso PC a C18:2, PC ae C44:3) previously associated with melanoma pathogenesis were identified as relevant in differentiating between disease stages.
Conclusion
The results further support the continued investigation of circulating plasma-derived EVs as biomarkers in melanoma. Furthermore, the potential of combined proteo-metabolomic signatures for differentiation between disease stages may provide valuable insights into early detection, prognosis, and personalised treatment strategies.
背景由于血浆衍生的细胞外囊泡（EVs）能够反映原发细胞并易于收集，因此被认为是黑色素瘤的新型生物标记物。本研究旨在找出能区分不同疾病阶段的新型EV生物标记物。方法采用尺寸排阻色谱法从36名黑色素瘤患者和13名健康对照者的血浆中分离出EVs。进行了蛋白质组学和代谢组学分析，并使用机器学习算法来识别潜在的蛋白质和代谢物，以区分不同疾病阶段的黑色素瘤患者的血浆衍生 EVs。蛋白质（APOC4、PRG4、PLG、TNC、VWF 和 SERPIND1）和代谢物（溶血 PC a C18:2、PC ae C44:3）以前曾与黑色素瘤发病机制相关，被认为与区分疾病分期有关。此外，结合蛋白质代谢组学特征区分疾病分期的潜力可为早期检测、预后和个性化治疗策略提供有价值的见解。
{"title":"Proteomic and metabolomic profiles of plasma-derived Extracellular Vesicles differentiate melanoma patients from healthy controls","authors":"SM Bollard , J Howard , C Casalou , BS Kelly , K O'Donnell , G Fenn , J O'Reilly , R Milling , M Shields , M Wilson , A Ajaykumar , K Triana , K Wynne , DJ Tobin , PA Kelly , A McCann , SM Potter","doi":"10.1016/j.tranon.2024.102152","DOIUrl":"10.1016/j.tranon.2024.102152","url":null,"abstract":"<div><h3>Background</h3><div>Plasma-derived Extracellular Vesicles (EVs) have been suggested as novel biomarkers in melanoma, due to their ability to reflect the cell of origin and ease of collection. This study aimed to identify novel EV biomarkers that can discriminate between disease stages. This was achieved by characterising the plasma-derived EVs of patients with melanoma, and comparing their proteomic and metabolomic profile to those from healthy controls.</div></div><div><h3>Methods</h3><div>EVs were isolated from the plasma of 36 patients with melanoma and 13 healthy controls using Size Exclusion Chromatography. Proteomic and Metabolomic Analyses were performed, and machine learning algorithms were used to identify potential proteins and metabolites to differentiate the plasma-derived EVs from melanoma patients of different disease stages.</div></div><div><h3>Results</h3><div>The concentration and size of the EV population isolated was similar between groups. Proteins (APOC4, PRG4, PLG, TNC, VWF and SERPIND1) and metabolites (lyso PC a C18:2, PC ae C44:3) previously associated with melanoma pathogenesis were identified as relevant in differentiating between disease stages.</div></div><div><h3>Conclusion</h3><div>The results further support the continued investigation of circulating plasma-derived EVs as biomarkers in melanoma. Furthermore, the potential of combined proteo-metabolomic signatures for differentiation between disease stages may provide valuable insights into early detection, prognosis, and personalised treatment strategies.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"50 ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2024-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142422507","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}
Pub Date : 2024-10-13DOI: 10.1016/j.tranon.2024.102156
Rong Qin , Xirui Fan , Yun Huang , Sijing Chen , Rui Ding , Ying Yao , Rui Wu , Yiyao Duan , Xiang Li , Hameed Ullah Khan , Jun Hu , Hui Wang
Colorectal cancer (CRC), with the incidence and mortality rising on a yearly basis, greatly threatens people's health. It is considered an important hallmark of tumorigenesis that aberrant glucose metabolism in cancer cells, particularly the Warburg effect. In CRC, the Warburg effect predominantly influences cancer development and progression via its involvement in the glycolytic pathway regarding cell metabolism. The critical mechanisms underlying this process include key glycolytic enzymes, transport proteins, regulatory molecules, and signaling pathways. Furthermore, targeting the reprogrammed glucose metabolism in cancer cells can be potentially used for CRC treatment. However, the mechanisms driving CRC onset and progression, especially in relation to glucose metabolism reprogramming, are not fully understood and represent an emerging field of research. The review aims at providing new insights into the role that glucose metabolism reprogramming plays in the progression of CRC progression together with its resistance to treatment. Ultimately, these insights strive to diminish the risks of CRC metastasis and recurrence.
{"title":"Role of glucose metabolic reprogramming in colorectal cancer progression and drug resistance","authors":"Rong Qin , Xirui Fan , Yun Huang , Sijing Chen , Rui Ding , Ying Yao , Rui Wu , Yiyao Duan , Xiang Li , Hameed Ullah Khan , Jun Hu , Hui Wang","doi":"10.1016/j.tranon.2024.102156","DOIUrl":"10.1016/j.tranon.2024.102156","url":null,"abstract":"<div><div>Colorectal cancer (CRC), with the incidence and mortality rising on a yearly basis, greatly threatens people's health. It is considered an important hallmark of tumorigenesis that aberrant glucose metabolism in cancer cells, particularly the Warburg effect. In CRC, the Warburg effect predominantly influences cancer development and progression via its involvement in the glycolytic pathway regarding cell metabolism. The critical mechanisms underlying this process include key glycolytic enzymes, transport proteins, regulatory molecules, and signaling pathways. Furthermore, targeting the reprogrammed glucose metabolism in cancer cells can be potentially used for CRC treatment. However, the mechanisms driving CRC onset and progression, especially in relation to glucose metabolism reprogramming, are not fully understood and represent an emerging field of research. The review aims at providing new insights into the role that glucose metabolism reprogramming plays in the progression of CRC progression together with its resistance to treatment. Ultimately, these insights strive to diminish the risks of CRC metastasis and recurrence.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"50 ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2024-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142422869","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}
Pub Date : 2024-10-13DOI: 10.1016/j.tranon.2024.102154
Weina Yang , Chengyuan Qian , Jiamin Luo , Chuan Chen , Yan Feng , Nan Dai , Xuemei Li , He Xiao , Yuxin Yang , Mengxia Li , Chunxue Li , Dong Wang
Background
Intravenous immune checkpoint inhibitors (ICIs) have shown efficacy in treating locally advanced rectal cancer (LARC), but concerns about systemic toxicity persist. This study developed a unique approach termed chemo-immuno-embolization with transcatheter rectal arterial intervention (CIETAI), aiming to enhance the anti-tumor response while minimizing systemic toxicity.
Method
This is a prospective, single-arm, phase II clinical trial conducted in Daping hospital. Patients with previously untreated stage II/III LARC underwent preoperative CIETAI combined with PD-1 inhibitor tislelizumab plus oxaliplatin, followed by standard concomitant chemoradiotherapy (capecitabine and 50.4 Gy radiation). Intravenous tislelizumab was administered for an additional two cycles.
Results
Between January 2023 and December 2023, a total of 38 patients were enrolled. As the primary endpoint, 17 (44.74 %) patients achieved pathological complete response (TRG0), with a major pathologic response (MPR) rate of 65.79 %. The anal preservation rate was 84.21 % (32/38), and importantly, 15 of 21 patients with low rectal cancer achieved organ preservation with functional maintenance. Eight patients experienced grade 3–4 adverse events (AEs). All immune-related AEs were grade 1–2, with the most common being endocrine toxicity (5/6, 83.33 %). No grade 5 AEs occurred.
Conclusion
This study provides preliminary evidence supporting the safety and efficacy of intraarterial tislelizumab delivery in the neoadjuvant setting for LARC. These promising results encourage further exploration in larger cohorts to validate the clinical impact of this novel CIETAI strategy.
{"title":"First in human intraarterial delivery of tislelizumab for the treatment of pMMR locally advanced rectal cancer: A single-arm, open label, phase II clinical trial","authors":"Weina Yang , Chengyuan Qian , Jiamin Luo , Chuan Chen , Yan Feng , Nan Dai , Xuemei Li , He Xiao , Yuxin Yang , Mengxia Li , Chunxue Li , Dong Wang","doi":"10.1016/j.tranon.2024.102154","DOIUrl":"10.1016/j.tranon.2024.102154","url":null,"abstract":"<div><h3>Background</h3><div>Intravenous immune checkpoint inhibitors (ICIs) have shown efficacy in treating locally advanced rectal cancer (LARC), but concerns about systemic toxicity persist. This study developed a unique approach termed chemo-immuno-embolization with transcatheter rectal arterial intervention (CIETAI), aiming to enhance the anti-tumor response while minimizing systemic toxicity.</div></div><div><h3>Method</h3><div>This is a prospective, single-arm, phase II clinical trial conducted in Daping hospital. Patients with previously untreated stage II/III LARC underwent preoperative CIETAI combined with PD-1 inhibitor tislelizumab plus oxaliplatin, followed by standard concomitant chemoradiotherapy (capecitabine and 50.4 Gy radiation). Intravenous tislelizumab was administered for an additional two cycles.</div></div><div><h3>Results</h3><div>Between January 2023 and December 2023, a total of 38 patients were enrolled. As the primary endpoint, 17 (44.74 %) patients achieved pathological complete response (TRG0), with a major pathologic response (MPR) rate of 65.79 %. The anal preservation rate was 84.21 % (32/38), and importantly, 15 of 21 patients with low rectal cancer achieved organ preservation with functional maintenance. Eight patients experienced grade 3–4 adverse events (AEs). All immune-related AEs were grade 1–2, with the most common being endocrine toxicity (5/6, 83.33 %). No grade 5 AEs occurred.</div></div><div><h3>Conclusion</h3><div>This study provides preliminary evidence supporting the safety and efficacy of intraarterial tislelizumab delivery in the neoadjuvant setting for LARC. These promising results encourage further exploration in larger cohorts to validate the clinical impact of this novel CIETAI strategy.</div></div><div><h3>Trial registration</h3><div>ClinicalTrials.gov Identifier: NCT05957016.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"50 ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2024-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142422516","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}
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