Theranostics最新文献

{"title":"Development and preclinical characterization of a novel radiotheranostic EphA2-targeting bicyclic peptide.","authors":"Mohamed El Fakiri, Anusha R Regupathy, Lisa Uhlmann, Nawal Ayada, Nicolas M Geis, Lisa-Charlotte Domogalla, Johanna Lahdenranta, Ben Blakeman, Francesca Wood, Philipp T Meyer, Philip Huxley, Matthias Eder, Gemma E Mudd, Ann-Christin Eder","doi":"10.7150/thno.96641","DOIUrl":"10.7150/thno.96641","url":null,"abstract":"<p><p>Erythropoietin-producing hepatocellular receptor A2 (EphA2), is a receptor tyrosine kinase involved in cell-cell interactions. It is known to be overexpressed in various tumors and is associated with poor prognosis. EphA2 has been proposed as a target for theranostic applications. Low molecular weight peptide-based scaffolds with low nanomolar affinities have been shown to be ideal in such applications. Bicyclic peptides have emerged as an alternative to traditional peptides for this purpose, offering affinities comparable to antibodies due to their constrained nature, along with high tissue penetration, and improved stability compared to linear counterparts. This study presents the development and comprehensive <i>in vitro</i> and <i>in vivo</i> preclinical evaluation of BCY18469, a novel EphA2-targeting bicyclic peptide-based radiotheranostic agent. <b>Methods:</b> The EphA2-targeting Bicycle^® peptide BCY18469 was identified through phage-display and chemically optimized. BCY18469 was radiolabeled with ⁶⁸Ga, ¹⁷⁷Lu and ¹¹¹In. The physicochemical properties, binding affinity and internalization as well as specificity of the peptide were evaluated <i>in vitro</i>. <i>In vivo</i> PET/MR and SPECT/CT imaging studies were performed using [⁶⁸Ga]Ga-BCY18469 and [¹¹¹In]In-BCY18469, respectively, along with biodistribution of [¹⁷⁷Lu]Lu-BCY18469 up to 24 h post injection in HT1080- and PC-3-tumor bearing BALB/c nu/nu EphA2-overexpressing xenograft mouse models. <b>Results:</b> The EphA2-targeting bicyclic peptide BCY18469 showed high binding affinity toward human and mouse EphA2 (1.9 and 3.8 nM, respectively). BCY18469 specifically bound and internalized into EphA2-expressing HT1080 cells. Imaging studies showed high tumor enrichment at early time-points (SUV of 1.7 g/mL at 1 h p.i. and 1.2 g/mL at 2 h p.i. in PET/MRI, HT1080 xenograft) with tumor contrast as early as 5 min p.i. and kidney-mediated clearance. Biodistribution studies revealed high early tumor uptake (19.5 ± 3.5 %ID/g at 1 h p.i., HT1080 xenograft) with SPECT/CT imaging further confirming these findings (5.7 ± 1.5 %ID/g at 1 h p.i., PC-3 xenograft). <b>Conclusion:</b> BCY18469 demonstrated high affinity, specific targeting of EphA2, a favorable biodistribution profile, and clearance through renal pathways. These findings underscore the potentially important role of bicyclic peptides in advancing radiotheranostic approaches and encourage additional translational research.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11373624/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142141149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of m6A-associated membraneless organelles in the RNA metabolism processes and human diseases.","authors":"Fang-Tian Bu, Hai-Yan Wang, Chao Xu, Kang-Li Song, Zhen Dai, Lin-Ting Wang, Jie Ying, Jianxiang Chen","doi":"10.7150/thno.99019","DOIUrl":"10.7150/thno.99019","url":null,"abstract":"<p><p><i>N</i>6-methyladenosine (m6A) is the most abundant post-transcriptional dynamic RNA modification process in eukaryotes, extensively implicated in cellular growth, embryonic development and immune homeostasis. One of the most profound biological functions of m6A is to regulate RNA metabolism, thereby determining the fate of RNA. Notably, the regulation of m6A-mediated organized RNA metabolism critically relies on the assembly of membraneless organelles (MLOs) in both the nucleus and cytoplasm, such as nuclear speckles, stress granules and processing bodies. In addition, m6A-associated MLOs exert a pivotal role in governing diverse RNA metabolic processes encompassing transcription, splicing, transport, decay and translation. However, emerging evidence suggests that dysregulated m6A levels contribute to the formation of pathological condensates in a range of human diseases, including tumorigenesis, reproductive diseases, neurological diseases and respiratory diseases. To date, the molecular mechanism by which m6A regulates the aggregation of biomolecular condensates associated with RNA metabolism is unclear. In this review, we comprehensively summarize the updated biochemical processes of m6A-associated MLOs, particularly focusing on their impact on RNA metabolism and their pivotal role in disease development and related biological mechanisms. Furthermore, we propose that m6A-associated MLOs could serve as predictive markers for disease progression and potential drug targets in the future.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11373618/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142141182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of Toll-like receptor 2 promotes mesenchymal stem/stromal cell-mediated immunoregulation and angiostasis through AKR1C1.","authors":"Jung Hwa Ko, Hyun Ju Lee, Chang Ho Yoon, Yoo Rim Choi, Jin Suk Ryu, Joo Youn Oh","doi":"10.7150/thno.100327","DOIUrl":"10.7150/thno.100327","url":null,"abstract":"<p><p><b>Background:</b> Mesenchymal stem/stromal cells (MSCs) maintain tissue homeostasis in response to microenvironmental perturbations. Toll-like receptors (TLRs) are key sensors for exogenous and endogenous signals produced during injury. In this study, we aimed to investigate whether TLRs affect the homeostatic functions of MSCs after injury. <b>Methods:</b> We examined the expression of TLR2, TLR3 and TLR4 in MSCs, and analyzed the functional significance of TLR2 activation using single-cell RNA sequencing. Additionally, we investigated the effects and mechanisms of TLR2 and its downstream activation in MSCs on the MSCs themselves, on monocytes/macrophages, and in a mouse model of sterile injury-induced inflammatory corneal angiogenesis. <b>Results:</b> MSCs expressed TLR2, which was upregulated by monocytes/macrophages. Activation of TLR2 in MSCs promoted their immunoregulatory and angiostatic functions in monocytes/macrophages and in mice with inflammatory corneal angiogenesis, whereas TLR2 inhibition attenuated these functions. Single-cell RNA sequencing revealed <i>AKR1C1</i>, a gene encoding aldo-keto reductase family 1 member C1, as the most significantly inducible gene in MSCs upon TLR2 stimulation, though its stimulation did not affect cell compositions. AKR1C1 protected MSCs against ferroptosis, increased secretion of anti-inflammatory cytokines, and enhanced their ability to drive monocytes/macrophages towards immunoregulatory phenotypes, leading to the amelioration of inflammatory corneal neovascularization in mice. <b>Conclusion:</b> Our findings suggest that activation of TLR2-AKR1C1 signaling in MSCs serves as an important pathway for the survival and homeostatic activities of MSCs during injury.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11373616/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142141146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Apoptotic vesicle-mediated senolytics requires mechanical loading.","authors":"Zhulin Xue, Yexiang Jiang, Bowen Meng, Lu Lu, Meng Hao, Yi Zhang, Songtao Shi, Zili Li, Xueli Mao","doi":"10.7150/thno.98763","DOIUrl":"10.7150/thno.98763","url":null,"abstract":"<p><p><b>Rationale:</b> Mechanical force plays crucial roles in extracellular vesicle biogenesis, release, composition and activity. However, it is unknown whether mechanical force regulates apoptotic vesicle (apoV) production. <b>Methods:</b> The effects of mechanical unloading on extracellular vesicles of bone marrow were evaluated through morphology, size distribution, yield, and protein mass spectrometry analysis using hindlimb unloading (HU) mouse model. Apoptosis resistance and aging related phenotype were assessed using HU mouse model <i>in vivo</i> and cell microgravity model <i>in vitro.</i> The therapeutic effects of apoVs on HU mouse model were assessed by using microcomputed tomography, histochemical and immunohistochemical, as well as histomorphometry analyses. SiRNA and chemicals were used for gain and loss-of-function assay. <b>Results:</b> In this study, we show that loss of mechanical force led to cellular apoptotic resistance and aging related phenotype, thus reducing the number of apoVs in the circulation due to down-regulated expression of Piezo1 and reduced calcium influx. And systemic infusion of apoVs was able to rescue Piezo1 expression and calcium influx, thereby, rescuing mechanical unloading-induced cellular apoptotic resistance, senescent cell accumulation. <b>Conclusions:</b> This study identified a previously unknown role of mechanical force in maintaining apoptotic homeostasis and eliminating senescent cells. Systemic infusion of mesenchymal stem cell-derived apoVs can effectively rescue apoptotic resistance and eliminate senescent cells in mechanical unloading mice.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11373628/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142141147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A relay-type innate immunity activation strategy involving water-soluble NIR-II AIEgen for boosted tumor photo-immunotherapy.","authors":"Shanshan Liu, Yan Sun, Dingyuan Yan, Wen Song, Jiajia Fu, Shanyong Wang, Tianhao Yang, Jun Zhu, Dongxia Zhu, Dong Wang, Feifan Zhou, Ben Zhong Tang","doi":"10.7150/thno.95724","DOIUrl":"10.7150/thno.95724","url":null,"abstract":"<p><p><b>Background:</b> Effective innate immunity activation could dramatically improve the anti-tumor efficacy and increase the beneficiary population of immunotherapy. However, the anti-tumor effect of unimodal immunotherapy is still not satisfactory. <b>Methods:</b> Herein, a novel relay-type innate immunity activation strategy based on photo-immunotherapy mediated by a water-soluble aggregation-induced emission luminogen, PEG₄₂₀-TQ, with the assistant of toll-like receptor 7 (TLR-7) agonist, imiquimod (R837), was developed and constructed. <b>Results:</b> The strategy could promote tumor cells to undergo immunogenic cell death (ICD) induced by the well-designed PEG₄₂₀-TQ@R837 (PTQ@R) nanoplatform under light irradiation, which in turn enhanced the infiltration of immune cells and the activation of innate immune cells to achieve the first innate immunity activation. The second innate immunity activation was subsequently achieved by drug delivery of R837 <i>via</i> apoptotic bodies (ApoBDs), further enhancing the anti-tumor activity of infiltrated immune cells. <b>Conclusion:</b> The strategy ultimately demonstrated robust innate immunity activation and achieved excellent performance against tumor growth and metastasis. The construction of the relay-type innate immunity activation strategy could provide a new idea for the application of immunotherapy in clinical trials.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11373630/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142141145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel assessment of whole-mount Gleason grading in prostate cancer to identify candidates for radical prostatectomy: a machine learning-based multiomics study.","authors":"Jing Ning, Clemens P Spielvogel, David Haberl, Karolina Trachtova, Stefan Stoiber, Sazan Rasul, Vojtech Bystry, Gabriel Wasinger, Pascal Baltzer, Elisabeth Gurnhofer, Gerald Timelthaler, Michaela Schlederer, Laszlo Papp, Helga Schachner, Thomas Helbich, Markus Hartenbach, Bernhard Grubmüller, Shahrokh F Shariat, Marcus Hacker, Alexander Haug, Lukas Kenner","doi":"10.7150/thno.96921","DOIUrl":"10.7150/thno.96921","url":null,"abstract":"<p><p><b>Purpose</b>: This study aims to assess whole-mount Gleason grading (GG) in prostate cancer (PCa) accurately using a multiomics machine learning (ML) model and to compare its performance with biopsy-proven GG (bxGG) assessment. <b>Materials and Methods</b>: A total of 146 patients with PCa recruited in a pilot study of a prospective clinical trial (NCT02659527) were retrospectively included in the side study, all of whom underwent ⁶⁸Ga-PSMA-11 integrated positron emission tomography (PET) / magnetic resonance (MR) before radical prostatectomy (RP) between May 2014 and April 2020. To establish a multiomics ML model, we quantified PET radiomics features, pathway-level genomics features from whole exome sequencing, and pathomics features derived from immunohistochemical staining of 11 biomarkers. Based on the multiomics dataset, five ML models were established and validated using 100-fold Monte Carlo cross-validation. <b>Results</b>: Among five ML models, the random forest (RF) model performed best in terms of the area under the curve (AUC). Compared to bxGG assessment alone, the RF model was superior in terms of AUC (0.87 vs 0.75), specificity (0.72 vs 0.61), positive predictive value (0.79 vs 0.75), and accuracy (0.78 vs 0.77) and showed slightly decreased sensitivity (0.83 vs 0.89) and negative predictive value (0.80 vs 0.81). Among the feature categories, bxGG was identified as the most important feature, followed by pathomics, clinical, radiomics and genomics features. The three important individual features were bxGG, PSA staining and one intensity-related radiomics feature. <b>Conclusion</b>: The findings demonstrate a superior assessment of the developed multiomics-based ML model in whole-mount GG compared to the current clinical baseline of bxGG. This enables personalized patient management by identifying high-risk PCa patients for RP.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11373617/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142141144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The biphasic role of Hspb1 on ferroptotic cell death in Parkinson's disease.","authors":"Jieyi Meng, Jinyu Fang, Yutong Bao, Huizhu Chen, Xiaodan Hu, Ziyuan Wang, Man Li, Quancheng Cheng, Yaqiong Dong, Xiaoda Yang, Yushu Zou, Dongyu Zhao, Jiping Tang, Weiguang Zhang, Chunhua Chen","doi":"10.7150/thno.98457","DOIUrl":"10.7150/thno.98457","url":null,"abstract":"<p><p><b>Rationale</b>: Ferroptosis-driven loss of dopaminergic neurons plays a pivotal role in the pathogenesis of Parkinson's disease (PD). In PD patients, Hspb1 is commonly observed at abnormally high levels in the substantia nigra. The precise consequences of Hspb1 overexpression in PD, however, have yet to be fully elucidated. <b>Methods</b>: We used human iPSC-derived dopaminergic neurons and Coniferaldehyde (CFA)-an Nrf2 agonist known for its ability to cross the blood-brain barrier-to investigate the role of Hspb1 in PD. We examined the correlation between Hspb1 overexpression and Nrf2 activation and explored the transcriptional regulation of Hspb1 by Nrf2. Gene deletion techniques were employed to determine the necessity of Nrf2 and Hspb1 for CFA's neuroprotective effects. <b>Results</b>: Our research demonstrated that Nrf2 can upregulate the transcription of Hspb1 by directly binding to its promoter. Deletion of either Nrf2 or Hspb1 gene abolished the neuroprotective effects of CFA. The Nrf2-Hspb1 pathway, newly identified as a defense mechanism against ferroptosis, was shown to be essential for preventing neurodegeneration progression. Additionally, we discovered that prolonged overexpression of Hspb1 leads to neuronal death and that Hspb1 released from ruptured cells can trigger secondary cell death in neighboring cells, exacerbating neuroinflammatory responses. <b>Conclusions</b>: These findings highlight a biphasic role of Hspb1 in PD, where it initially provides neuroprotection through the Nrf2-Hspb1 pathway but ultimately contributes to neurodegeneration and inflammation when overexpressed. Understanding this dual role is crucial for developing therapeutic strategies targeting Hspb1 and Nrf2 in PD.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11373631/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142141180","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rbm24/Notch1 signaling regulates adult neurogenesis in the subventricular zone and mediates Parkinson-associated olfactory dysfunction.","authors":"Ke Wang, Xing-Yang Liu, Sui-Feng Liu, Xiao-Xia Wang, Yi-Hua Wei, Jun-Rong Zhu, Jing Liu, Xiu Qin Xu, Lei Wen","doi":"10.7150/thno.96045","DOIUrl":"10.7150/thno.96045","url":null,"abstract":"<p><p><b>Rationale:</b> Adult neurogenesis in the subventricular zone (SVZ) is essential for maintaining neural homeostasis, and its dysregulation contributes to anosmia and delayed tissue healing in neurological disorders, such as Parkinson's disease (PD). Despite intricate regulatory networks identified in SVZ neurogenesis, the molecular mechanisms dynamically maintaining neural stem/progenitor cells (NSPCs) in response to physiological and pathological stimuli remain incompletely elucidated. <b>Methods:</b> We generated an RNA binding motif protein 24 (Rbm24) knockout model to investigate its impact on adult neurogenesis in the SVZ, employing immunofluorescence, immunoblot, electrophysiology, RNA-sequencing, and <i>in vitro</i> experiments. Further investigations utilized a PD mouse model, along with genetic and pharmacological manipulations, to elucidate Rbm24 involvement in PD pathology. <b>Results:</b> Rbm24, a multifaceted post-transcriptional regulator of cellular homeostasis, exhibited broad expression in the SVZ from development to aging. Deletion of Rbm24 significantly impaired NSPC proliferation in the adult SVZ, ultimately resulting in collapsed neurogenesis in the olfactory bulb. Notably, Rbm24 played a specific role in maintaining Notch1 mRNA stability in adult NSPCs. The Rbm24/Notch1 signaling axis was significantly downregulated in the SVZ of PD mice. Remarkably, overexpression of Rbm24 rescued disruption of adult neurogenesis and olfactory dysfunction in PD mice, and these effects were hindered by DAPT, a potent inhibitor of Notch1. <b>Conclusions:</b> Our findings highlight the critical role of the Rbm24/Notch1 signaling axis in regulating adult SVZ neurogenesis under physiological and pathological circumstances. This provides valuable insights into the dynamic regulation of NSPC homeostasis and offers a potential targeted intervention for PD and related neurological disorders.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11303084/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141902982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of <i>TP53</i> loss-of-function alterations on the response to PSMA radioligand therapy in metastatic castration-resistant prostate cancer patients.","authors":"Peter H J Slootbeek, María Victoria Luna-Velez, Bastiaan M Privé, Maarten J van der Doelen, Iris S H Kloots, Samhita Pamidimarri Naga, Hilde E Onstenk, James Nagarajah, Harm Westdorp, Inge M van Oort, Leonie I Kroeze, Jack A Schalken, Haiko J Bloemendal, Niven Mehra","doi":"10.7150/thno.96322","DOIUrl":"10.7150/thno.96322","url":null,"abstract":"<p><p><b>Rationale:</b> PSMA-targeting radioligand therapy (PSMA-RLT) has shown promise in metastatic castration-resistant prostate cancer (mCRPC), particularly in PSMA-avid tumours. However, predicting response remains challenging. Preclinical data suggests aberrant p53-signalling as a predictor of poor response. <b>Methods:</b> The patient population of this pre-planned retrospective cohort study consists of 96 patients with mCRPC who underwent treatment with PSMA-RLT and were molecularly profiled by whole-genome sequencing and or targeted next-generation sequencing. Response to PSMA-RLT was assessed per molecular subtype, including <i>TP53</i>-mutational status. <b>Results:</b> Patients with <i>TP53</i> loss-of-function alterations had a shorter median progression-free survival (3.7 versus 6.2 months, <i>P</i><0.001), a lower median PSA change (-55% vs. -75%, <i>P</i>=0.012) and shorter overall survival from initiation of PMSA-RLT (7.6 vs. 13.9 months, <i>P</i>=0.003) compared to <i>TP53</i>-wildtype patients. Pathogenic alterations in <i>AR</i>, <i>MYC</i>, <i>BRCA1</i>, or <i>BRCA2</i> as well as in genes linked to the PI3K or MAPK pathways or genes involved in homologous recombination repair, were not associated with response. Only lactate dehydrogenase was, alongside <i>TP53</i>-status, significantly associated with response. Transcriptome analysis of 21 patients, identified six p53 signalling genes whose low expression was associated to a shorter progression-free survival (<i>P</i><0.05). <b>Conclusion:</b> <i>TP53</i> loss-of-function may serve as a prognostic factor for PSMA-RLT outcomes in patients with mCRPC.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11373632/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142141161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In-depth cross-validation of human and mouse CD4-specific minibodies for noninvasive PET imaging of CD4⁺ cells and response prediction to cancer immunotherapy.","authors":"Stefania Pezzana, Simone Blaess, Jule Kortendieck, Nicole Hemmer, Bredi Tako, Claudia Pietura, Lara Ruoff, Simon Riel, Martin Schaller, Irene Gonzalez-Menendez, Leticia Quintanilla-Martinez, Alessandro Mascioni, Argin Aivazian, Ian Wilson, Andreas Maurer, Bernd J Pichler, Manfred Kneilling, Dominik Sonanini","doi":"10.7150/thno.95173","DOIUrl":"10.7150/thno.95173","url":null,"abstract":"<p><p>Increasing evidence emphasizes the pivotal role of CD4⁺ T cells in orchestrating cancer immunity. Noninvasive <i>in vivo</i> imaging of the temporal dynamics of CD4⁺ T cells and their distribution patterns might provide novel insights into their effector and regulator cell functions during cancer immunotherapy (CIT). <b>Methods:</b> We conducted a comparative analysis of ⁸⁹Zr-labeled anti-mouse (m) and anti-human (h) CD4-targeting minibodies (Mbs) for <i>in vivo</i> positron emission tomography (PET)/magnetic resonance imaging (MRI) of CD4⁺ T cells in human xenografts, syngeneic tumor-bearing wild-type (WT), and human CD4⁺ knock-in (hCD4-KI) mouse models. <b>Results:</b> Both ⁸⁹Zr-CD4-Mbs yielded high radiolabeling efficiencies of >90%, immunoreactivities of >70%, and specific <i>in vitro</i> binding to their target antigens. The specificity of <i>in vivo</i> targeting of ⁸⁹Zr-hCD4-Mb was confirmed by PET/MRI, revealing ~4-fold greater ⁸⁹Zr-hCD4-Mb uptake in subcutaneous hCD4⁺ hematopoietic peripheral blood acute lymphoblastic leukemia tumors (HPB-ALL) than in solid hCD4^- diffuse histiocytic lymphomas (DHL) and ⁸⁹Zr-mCD4-Mb uptake in hCD4⁺ HPB-ALL tumors. In a comparative cross-validation study in anti-programmed death ligand (αPD-L1)/anti-4-1BB-treated orthotopic PyMT mammary carcinoma-bearing hCD4-KI and WT mice, we detected 2- to 3-fold enhanced species-specific ⁸⁹Zr-hCD4-Mb or ⁸⁹Zr-mCD4-Mb uptake within CD4⁺ cell-enriched secondary lymphatic organs (lymph nodes and spleens). The ⁸⁹Zr-hCD4-Mb uptake in the PyMT tumors was more pronounced in hCD4-KI mice compared to the WT control littermates. Most importantly, MC38 adenocarcinoma-bearing mice treated with a combination of αPD-L1 and anti-lymphocyte-activation gene 3 (αLag-3) antibodies exhibited ~1.4-fold higher ⁸⁹Zr-mCD4-Mb uptake than mice that were not responsive to therapy or sham-treated mice. <b>Conclusion:</b> CD4 PET/MRI enabled monitoring of the CD4⁺ cell distribution in secondary lymphatic organs and the tumor microenvironment, capable of predicting sensitivity to CIT. Our imaging approach will provide deeper insights into the underlying molecular mechanisms of CD4-directed cancer immunotherapies in preclinical mouse models and is applicable for clinical translation.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11373626/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142141162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}