Theranostics最新文献

{"title":"Empowering brain tumor management: chimeric antigen receptor macrophage therapy","authors":"Fan Feng, Jianyu Shen, Qichao Qi, Yulin Zhang, Shilei Ni","doi":"10.7150/thno.98290","DOIUrl":"https://doi.org/10.7150/thno.98290","url":null,"abstract":"Brain tumors pose formidable challenges in oncology due to the intricate biology and the scarcity of effective treatment modalities. The emergence of immunotherapy has opened new avenues for innovative therapeutic strategies. Chimeric antigen receptor, originally investigated in T cell-based therapy, has now expanded to encompass macrophages, presenting a compelling avenue for augmenting anti-tumor immune surveillance. This emerging frontier holds promise for advancing the repertoire of therapeutic options against brain tumors, offering potential breakthroughs in combating the formidable malignancies of the central nervous system. Tumor-associated macrophages constitute a substantial portion, ranging from 30% to 50%, of the tumor tissue and exhibit tumor-promoting phenotypes within the immune-compromised microenvironment. Constructing CAR-macrophages can effectively repolarize M2-type macrophages towards an M1-type phenotype, thereby eliciting potent anti-tumor effects. CAR-macrophages can recruit T cells to the brain tumor site, thereby orchestrating a remodeling of the immune niche to effectively inhibit tumor growth. In this review, we explore the potential limitations as well as strategies for optimizing CAR-M therapy, offering insights into the future direction of this innovative therapeutic approach.","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142186947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The m6A reader YTHDC2 promotes the pathophysiology of temporal lobe epilepsy by modulating SLC7A11-dependent glutamate dysregulation in astrocytes","authors":"Kai Zhang, Zhiquan Yang, Zhuanyi Yang, Liangchao Du, Yu Zhou, Shiyu Fu, Xiaoyue Wang, Xing Li, Dingyang Liu, Xinghui He","doi":"10.7150/thno.100703","DOIUrl":"https://doi.org/10.7150/thno.100703","url":null,"abstract":"<b>Rationale:</b> Epilepsy affects over 70 million people globally, with temporal lobe epilepsy with hippocampal sclerosis (TLE-HS) often progressing to a drug-resistant state. Recent research has highlighted the role of reactive astrocytes and glutamate dysregulation in epilepsy pathophysiology. This study aims to investigate the involvement of astrocytic xCT, a glutamate-cystine antiporter, and its regulation by the m6A reader protein YTHDC2 in TLE-HS./n<b>Methods:</b> A pilocarpine-induced epilepsy model in mice was used to study the role of xCT in reactive astrocytes. The expression of xCT and its regulation by YTHDC2 were assessed through various molecular and cellular techniques. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were used to measure mRNA and protein levels of xCT and YTHDC2, respectively; immunofluorescence was utilized to visualize their localization and expression in astrocytes. <i>In vivo</i> glutamate measurements were conducted using microdialysis to monitor extracellular glutamate levels in the hippocampus. RNA immunoprecipitation-qPCR (RIP-qPCR) was performed to investigate the binding of YTHDC2 to SLC7A11 mRNA, while methylated RNA immunoprecipitation-qPCR (MeRIP-qPCR) was performed to quantify m6A modifications on SLC7A11 mRNA. A dual-luciferase reporter assay was conducted to assess the effect of m6A modifications on SLC7A11 mRNA translation, and polysome profiling was employed to evaluate the translational efficiency of SLC7A11 mRNA. Inhibition experiments involved shRNA-mediated knockdown of SLC7A11 (commonly known as xCT) and YTHDC2 expression in astrocytes. Video-electroencephalogram (EEG) recordings were used to monitor seizure activity in mice./n<b>Results:</b> The xCT transporter in reactive astrocytes significantly contributes to elevated extracellular glutamate levels, enhancing neuronal excitability and seizure activity. Increased xCT expression is influenced by the m6A reader protein YTHDC2, which regulates its expression through m6A methylation. Inhibition of xCT or YTHDC2 in astrocytes reduces glutamate levels and effectively controls seizures in a mouse model. Specifically, mice with SLC7A11- or YTHDC2-knockdown astrocytes showed decreased glutamate concentration in the hippocampus and reduced frequency and duration of epileptic seizures./n<b>Conclusions:</b> This study highlights the therapeutic potential of targeting YTHDC2 and xCT in reactive astrocytes to mitigate epilepsy. The findings provide a novel perspective on the mechanisms of glutamate dysregulation and their implications in seizure pathophysiology, suggesting that modulation of YTHDC2 and xCT could be a promising strategy for treating TLE.","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142186924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypoxia inducible factor (HIF) 3α prevents COPD by inhibiting alveolar epithelial cell ferroptosis via the HIF-3α-GPx4 axis","authors":"Junchao Jiang, Zhoude Zheng, Shengsong Chen, Jixiang Liu, Ju Jia, Yuhang Huang, Qing Liu, Chung Y Cheung, Don D Sin, Ting Yang, Chen Wang","doi":"10.7150/thno.99237","DOIUrl":"https://doi.org/10.7150/thno.99237","url":null,"abstract":"<b>Rationale:</b> COPD patients are largely asymptomatic until the late stages when prognosis is generally poor. In this study, we shifted the focus to pre-COPD and smoking stages, and found enrichment of hypoxia inducible factor (HIF)-3α is in pre-COPD samples. Smoking induced regional tissue hypoxia and emphysema have been found in COPD patients. However, the mechanisms underlying hypoxia especially HIF-3α and COPD have not been investigated./n<b>Methods:</b> We performed bulk-RNA sequencing on 36 peripheral lung tissue specimens from non-smokers, smokers, pre-COPD and COPD patients, and using “Mfuzz” algorithm to analysis the dataset dynamically. GSE171541 and EpCAM co-localization analyses were used to explore HIF-3α localization. Further, <i>Sftpc^Creert2/+R26^LSL-Hif3a</i> knock-in mice and small molecular inhibitors <i>in vitro</i> were used to explore the involvement of HIF-3α in the pathophysiology of COPD./n<b>Results:</b> Reactive oxygen species (ROS) and hypoxia were enriched in pre-COPD samples, and HIF-3α was downregulated in alveolar epithelial cells in COPD. <i>In vitro</i> experiments using lentivirus transfection, bulk-RNA seq, and RSL3 showed that the activation of the HIF-3α-GPx4 axis inhibited alveolar epithelial cell ferroptosis when treated with cigarettes smoking extracts (CSE). Further results from <i>Sftpc^Creert2/+R26^LSL-Hif3a</i> knock-in mice demonstrated overexpression of HIF-3α inhibited alveolar epithelial cells ferroptosis and prevented the decline of lung function./n<b>Conclusion:</b> Hypoxia and oxidation-related damage begins years before the onset of COPD symptoms, suggesting the imbalance and impairment of intracellular homeostatic system. The activation of the HIF-3α-GPx4 axis is a promising treatment target. By leveraging this comprehensive analysis method, more potential targets could be found and enhancing our understanding of the pathogenesis.","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142186962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Honokiol enhances the sensitivity of cetuximab in KRASG13D mutant colorectal cancer through destroying SNX3-retromer complex","authors":"Qianru Zhu, Ruonan Zhang, Xiaoqing Gu, Ziming Zhao, Quan Gao, Min Chen, Qibiao Wu, Tian Xie, Xinbing Sui","doi":"10.7150/thno.97180","DOIUrl":"https://doi.org/10.7150/thno.97180","url":null,"abstract":"<b><i>Rationale</i></b>: the proto-oncogene <i>KRAS</i> is frequently mutated in colorectal cancer (CRC), leading to inherent resistance against monoclonal antibodies targeting the epidermal growth factor receptor (EGFR), such as cetuximab. Therefore, addressing the primary resistance and expanding the indications for target therapy have become critical challenges./n<b><i>Methods</i></b>: the screening of a natural product library against KRAS mutant CRC cells was conducted, leading to the discovery of a small molecule compound that sensitive to the KRAS^G13D mutation site. The anti-tumor activity of this small molecule compound in combination with cetuximab was evaluated using the KRAS^G13D mutant CRC models both <i>in vivo</i> and <i>in vitro</i>. This evaluation includes an examination of its effects on cell proliferation, viability, apoptosis, cell cycle progression, and tumor growth. Furthermore, RNA sequencing, western blot analysis, immunofluorescence, real-time quantitative PCR, and pull-down assays were employed to explore the molecular mechanisms underlying the synergistic anti-tumor effect of this small molecule compound in combination with cetuximab./n<b><i>Results</i></b>: our study screened 882 compounds in KRAS mutant CRC cells and identified honokiol, a small molecule compound that exhibits specific sensitivity to KRAS^G13D mutant CRC cells. Furthermore, we revealed that the synergistic augmentation of cetuximab's sensitivity <i>in vivo</i> and <i>in vitro</i> models of KRAS^G13D mutant CRC in combination with honokiol. Mechanistically, honokiol suppresses SNX3-retromer mediated trafficking, thereby impeding lysosomal proteolytic capacity and inhibiting autophagy and macropinocytosis fluxes. Moreover, honokiol inhibits the conversion of RAS GDP to RAS GTP, heightening the susceptibility of KRAS^G13D CRC mutant cells to cetuximab./n<b><i>Conclusions</i></b>: honokiol enhances the sensitivity of cetuximab by destroying SNX3 retromer in KRAS^G13D mutant CRC preclinical model. These findings present a promising strategy for expanding the indications of target therapy in KRAS mutant colorectal cancer patients.","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142186961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Milk-derived extracellular vesicles enable gut-to-tumor oral delivery of tumor-activated doxorubicin prodrugs","authors":"Hochung Jang, Jiwoong Choi, Daeho Park, Geonhee Han, Eun Hye Kim, Kwangmeyung Kim, Sun Hwa Kim, Man Kyu Shim, Yoosoo Yang","doi":"10.7150/thno.97269","DOIUrl":"https://doi.org/10.7150/thno.97269","url":null,"abstract":"<b>Rationale:</b> Oral chemotherapy has been emerging as a hopeful therapeutic regimen for the treatment of various cancers because of its high safety and convenience, lower costs, and high patient compliance. Despite the current advancements in nanoparticle-mediated drug delivery, numerous anticancer drugs susceptible to the hostile gastrointestinal (GI) environment exhibit poor permeability across the intestinal epithelium, rendering them ineffective in providing therapeutic benefits. In this paper, we focus on harnessing milk-derived extracellular vesicles (mEVs) for gut-to-tumor oral drug delivery by leveraging their high bioavailability./n<b>Methods:</b> The tumor-activated prodrug (a cathepsin B-specific cleavable FRRG peptide and doxorubicin, FDX) is used as a model drug and is complexed with mEVs, resulting in FDX@mEVs. To verify stability in the GI tract, prolonged intestinal retention, and enhanced trans-epithelial transport via neonatal Fc receptor (FcRn)-mediated transcytosis, intestinal transport evaluation is conducted using <i>in vitro</i> intestinal barrier model and mouse model./n<b>Results</b>: FDX@mEVs form a stable nanostructure with an average diameter of 131.1 ± 70.5 nm and complexation processes do not affect the inherent properties of FDX. Orally administered FDX@mEVs show significantly improved bioavailability compared to uncomplexed FDX via FcRn-mediated transcytosis of mEVs resulting in increased tumor accumulation of FDX in tumor-bearing mouse model./n<b>Conclusions:</b> After oral administration of FDX@mEVs, it is observed that remarkable antitumor efficacy in colon tumor-bearing mice without adverse effects, such as body weight loss, liver/kidney dysfunction, and cardiotoxicity.","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142186958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lutetium-177-PSMA therapy for recurrent/metastatic salivary gland cancer: a prospective pilot study","authors":"Niels J. van Ruitenbeek, Maike J.M. Uijen, Chantal M.L. Driessen, Steffie M.B. Peters, Bastiaan M. Privé, Adriana C.H. van Engen-van Grunsven, Mark W. Konijnenberg, Martin Gotthardt, James Nagarajah, Carla M.L. van Herpen","doi":"10.7150/thno.99035","DOIUrl":"https://doi.org/10.7150/thno.99035","url":null,"abstract":"There is an urgent need for novel systemic therapies for recurrent/systemic salivary gland cancer, as current treatment options are scarce. [⁶⁸Ga]Ga-PSMA-11 PET/CT revealed relevant uptake of prostate-specific membrane antigen (PSMA) in adenoid cystic carcinoma (AdCC) and salivary duct carcinoma (SDC). Therefore, we assessed the safety, feasibility, efficacy and radiation dosimetry of [¹⁷⁷Lu]Lu-PSMA-I&amp;T treatment in AdCC and SDC patients in a prospective pilot study./n<b>Methods:</b> This single-center, single-arm study intended to include 10 recurrent/metastatic AdCC patients and five recurrent/metastatic SDC patients. AdCC patients could only participate in case of progressive and/or symptomatic disease. Patients required ≥ 1 lesion ≥ 1.5 cm with an SUV_max on [⁶⁸Ga]Ga-PSMA-11 PET/CT above liver SUV_mean. Patients were planned to receive four cycles ~ 7.4 GBq [¹⁷⁷Lu]Lu-PSMA-I&amp;T. In case of progressive disease per RECIST 1.1 at mid-treatment evaluation after two cycles, treatment was discontinued. Safety was the primary endpoint. Secondary endpoints included objective response rate (ORR), tumor- and organ-absorbed radiation doses and progression-free survival./n<b>Results:</b> After screening, 10 out of 15 (67%) AdCC and two out of 10 (20%) SDC patients were eligible. Two patients (17%) demonstrated grade 3 treatment-related toxicity: lymphocytopenia (8%) and hyponatremia (8%). No dose-limiting toxicities occurred. In the AdCC cohort, six patients (60%) completed the four treatment cycles. Due to progressive disease, treatment was discontinued after two cycles in three patients (30%) and after one cycle in one patient (10%). No objective responses were observed (ORR: 0%). Three AdCC patients (30%) showed stable disease ≥ 6 months (7, 17 and 23 months). None of the two SDC patients completed the treatment: one patient deteriorated after the first cycle, while the other had progressive disease after two cycles. The high screen failure rate due to insufficient PSMA uptake resulted in premature closure of the SDC cohort. Dosimetry revealed low tumor-absorbed doses (median 0.07 Gy/GBq, range 0.001-0.63 Gy/GBq)./n<b>Conclusions:</b> [¹⁷⁷Lu]Lu-PSMA-I&amp;T in AdCC and SDC patients was safe and generally well-tolerated. However, efficacy was limited, likely due to low tumor-absorbed doses. For SDC, [¹⁷⁷Lu]Lu-PSMA-I&amp;T appears unfeasible due to insufficient PSMA uptake.","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142186957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Parkin plays a crucial role in acute viral myocarditis by regulating mitophagy activity","authors":"Yixuan Qiu, Jing Xu, Yilian Chen, Yihao Wu, Yuan-nan Lin, Weike Liu, Zhening Wang, Yuqing Wu, Xinge Qian, Yue-Chun Li","doi":"10.7150/thno.97675","DOIUrl":"https://doi.org/10.7150/thno.97675","url":null,"abstract":"<b>Rationale:</b> Parkin (an E3 ubiquitin protein ligase) is an important regulator of mitophagy. However, the role of Parkin in viral myocarditis (VMC) remains unclear./n<b>Methods:</b> Coxsackievirus B3 (CVB3) infection was induced in mice to create VMC. Cardiac function and inflammatory response were evaluated by echocardiography, histological assessment, and molecular analyses. AAV9 (adeno-associated virus 9), transmission electron microscopy (TEM) and western blotting were used to investigate the mechanisms by which Parkin regulates mitophagy and cardiac inflammation./n<b>Results:</b> Our data indicated that Parkin- and BNIP3 (BCL2 interacting protein 3 like)-mediated mitophagy was activated in VMC mice and neonatal rat cardiac myocytes (NRCMs) infected with CVB3, which blocked autophagic flux by inhibiting autophagosome-lysosome fusion. Parkin silencing aggravated mortality and accelerated the development of cardiac dysfunction in CVB3-treated mice. While silencing of Parkin did not significantly increase inflammatory response through activating NF-κB pathway and production of inflammatory cytokines post-VMC, the mitophagy activity were reduced, which stimulated the accumulation of damaged mitochondria. Moreover, Parkin silencing exacerbated VMC-induced apoptosis. We consistently found that Parkin knockdown disrupted mitophagy activity and inflammatory response in NRCMs./n<b>Conclusion:</b> This study elucidated the important role of Parkin in maintaining cardiac function and inflammatory response by regulating mitophagy activity and the NF-κB pathway during acute VMC. Although the functional impact of mitophagy remains unclear, our findings suggest that Parkin silencing may accelerate VMC development.","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142186970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Theranostics with somatostatin receptor antagonists in SCLC: Correlation of 68Ga-SSO120 PET with immunohistochemistry and survival","authors":"Ilektra Antonia Mavroeidi, Anna Romanowicz, Tristan Haake, Johannes Wienker, Martin Metzenmacher, Kaid Darwiche, Filiz Oezkan, Servet Bölükbas, Martin Stuschke, Lale Umutlu, Marcel Opitz, Michael Nader, Rainer Hamacher, Jens Siveke, Jane Winantea, Wolfgang P. Fendler, Marcel Wiesweg, Wilfried E. E. Eberhardt, Ken Herrmann, Dirk Theegarten, Martin Schuler, Hubertus Hautzel, David Kersting","doi":"10.7150/thno.98819","DOIUrl":"https://doi.org/10.7150/thno.98819","url":null,"abstract":"<b>Rationale:</b> Positron Emission Tomography (PET) using the somatostatin receptor 2 (SSTR2)-antagonist satoreotide trizoxetan (⁶⁸Ga-SSO120) is a novel, promising imaging modality for small-cell lung cancer (SCLC), which holds potential for theranostic applications. This study aims to correlate uptake in PET imaging with SSTR2 expression in immunohistochemistry (IHC) and to assess the prognostic value of ⁶⁸Ga-SSO120 PET at initial staging of patients with SCLC./n<b>Methods:</b> We analyzed patients who underwent ⁶⁸Ga-SSO120 PET/CT during initial diagnostic workup of SCLC as part of institutional standard-of-care. SSTR2 expression in IHC was evaluated on a 4-level scale and correlated with normalized standardized uptake values and tumor-to-liver ratios (SUV_max and TLR_peak) in ⁶⁸Ga-SSO120 PET on a lesion level. Highest lesion SUV_max/TLR_peak per patient, SSTR2 score in IHC, M status according to TNM classification, and other parameters were analyzed for association with overall survival (OS) and time to treatment failure (TTF) by univariate, multivariate (cut-off values were identified on data for best separation), and stratified Cox regression./n<b>Results:</b> We included 54 patients (24 men/30 women, median age 65 years, 21 M0/33 M1 according to TNM classification). In 43 patients with available surplus tumor tissue samples, hottest lesion SUV_max/TLR_peak showed a significant correlation with the level of SSTR2-expression by tumor cells in IHC (Spearman's rho 0.86/0.81, both p &lt; 0.001; ANOVA p &lt; 0.001). High SSTR2 expression in IHC, ⁶⁸Ga-SSO120 SUV_max and TLR_peak of the hottest lesion per patient, whole-body TLR_mean, MTV, TLG, M status, and serum LDH showed a significant association with inferior TTF/OS in univariate analysis. In separate multivariate Cox regression (including sex, age, M stage, and LDH) higher hottest-lesion TLR_peak showed a significant association with shorter OS (HR = 0.26, 95%CI: 0.08-0.84, p = 0.02) and SSTR2 expression in IHC with significantly shorter TTF (HR = 0.24, 95%CI: 0.08-0.71, p = 0.001) and OS (HR = 0.22, 95%CI: 0.06-0.84, p = 0.03). In total, 12 patients (22.2%) showed low (&lt; 1), 21 (38.9%) intermediate (≥ 1 but &lt; 2), 14 (25.9%) high (≥ 2 but &lt; 5), and 7 (13.0%) very high (≥ 5) whole-body mean TLR_mean./n<b>Conclusion:</b> In patients with SCLC, SSTR2 expression assessed by ⁶⁸Ga-SSO120 PET and by IHC were closely correlated and associated with shorter survival. More than 75% of patients showed higher whole-body⁶⁸Ga-SSO120 tumor uptake than liver uptake and almost 40% high or very high uptake, possibly paving the way towards theranostic applications.","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142186959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clearance of senescent cells enhances skin wound healing in type 2 diabetic mice","authors":"Priyadarshani Nadeeshika Samarawickrama, Guiqin Zhang, Enfang Zhu, Xin Dong, Ayesha Nisar, Hong Zhu, Yuan Ma, Zheyan Zhou, Honglin Yang, Li Gui, Mei Cao, Wei Li, Yu Chang, Meiting Zi, Haoling Cui, Zhongping Duan, Xuan Zhang, Wen Li, Yonghan He","doi":"10.7150/thno.100991","DOIUrl":"https://doi.org/10.7150/thno.100991","url":null,"abstract":"<b>Background:</b> Diabetic foot ulcers (DFUs) pose a substantial healthcare challenge due to their high rates of morbidity, recurrence, disability, and mortality. Current DFU therapeutics continue to grapple with multiple limitations. Senescent cells (SnCs) have been found to have a beneficial effect on acute wound healing, however, their roles in chronic wounds, such as DFU, remain unclear./n<b>Methods and results:</b> We collected skin, fat, and muscle samples from clinical patients with DFU and lower limb fractures. RNA-sequencing combined with qPCR analyses on these samples demonstrate a significant accumulation of SnCs at DFU, as indicated by higher senescence markers (e.g., p16 and p21) and a senescence-associated secretory phenotype (SASP). We constructed a type 2 diabetic model of db/db mice, fed with a high-fat diet (Db-HFD), which were wounded using a 6 mm punch to the dorsal skin. HFD slightly affected wound healing in wild-type (WT) mice, but high glucose significantly delayed wound healing in the Db-HFD mice. We injected the mice with a previously developed fluorescent probe (XZ1208), which allows the detection of SnCs <i>in vivo</i>, and observed a strong senescence signal at the wound site of the Db-HFD mice. Contrary to the beneficial effects of SnCs in acute wound healing, our results demonstrated that clearance of SnCs using the senolytic compound ABT263 significantly accelerated wound healing in Db-HFD mice./n<b>Conclusion:</b> Collectively, these findings suggest that SnCs critically accumulate at wound sites, delaying the healing process in DFUs. Thus, targeting SnCs with senolytic therapy represents a promising approach for DFU treatment, potentially improving the quality of life for patients with DFUs.","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142186960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The heterobivalent (SSTR2/albumin) radioligand [67Cu]Cu-NODAGA-cLAB4-TATE enables efficient somatostatin receptor radionuclide theranostics","authors":"Martin Ullrich, Robert Wodtke, Florian Brandt, Robert Freudenberg, Jörg Kotzerke, Susan Richter, Klaus Kopka, Jens Pietzsch","doi":"10.7150/thno.100091","DOIUrl":"https://doi.org/10.7150/thno.100091","url":null,"abstract":"Somatostatin type 2 receptor (SSTR2) radionuclide therapy using β^- particle-emitting radioligands has entered clinical practice for the treatment of neuroendocrine neoplasms (NENs). Despite the initial success of [¹⁷⁷Lu]Lu‑DOTA-TATE, theranostic SSTR2 radioligands require improved pharmacokinetics and enhanced compatibility with alternative radionuclides. Consequently, this study evaluates the pharmacokinetic effects of the albumin-binding domain cLAB4 on theranostic performance of copper‑67-labeled NODAGA-TATE variants in an SSTR2-positive mouse pheochromocytoma (MPC) model./n<b>Methods:</b> Binding, uptake, and release of radioligands as well as growth-inhibiting effects were characterized in cells grown as monolayers and spheroids. Tissue pharmacokinetics, absorbed tumor doses, and projected human organ doses were determined from quantitative SPECT imaging in a subcutaneous tumor allograft mouse model. Treatment effects on tumor growth, leukocyte numbers, and renal albumin excretion were assessed./n<b>Results:</b> Both copper‑64- and copper‑67-labeled versions of NODAGA-TATE and NODAGA-cLAB4‑TATE showed similar SSTR2 binding affinity, but faster release from tumor cells compared to the clinical reference [¹⁷⁷Lu]Lu‑DOTA-TATE. The bifunctional SSTR2/albumin-binding radioligand [⁶⁷Cu]Cu‑NODAGA-cLAB4‑TATE showed both an improved uptake and prolonged residence time in tumors resulting in equivalent treatment efficacy to [¹⁷⁷Lu]Lu‑DOTA-TATE. Absorbed doses were well tolerated in terms of leukocyte counts and kidney function./n<b>Conclusion:</b> This preclinical study demonstrates therapeutic efficacy of [⁶⁷Cu]Cu‑NODAGA-cLAB4‑TATE in SSTR2-positive tumors. As an intrinsic radionuclide theranostic agent, the radioligand provides stable radiocopper complexes and high sensitivity in SPECT imaging for prospective determination and monitoring of therapeutic doses<i> in vivo</i>. Beyond that, copper‑64- and copper‑61-labeled versions offer possibilities for pre- and post-therapeutic PET. Therefore, NODAGA-cLAB4-TATE has the potential to advance clinical use of radiocopper in SSTR2-targeted cancer theranostics.","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142186948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}