Theranostics最新文献

{"title":"Association of integrated biomarkers and progression-free survival prediction in patients with gastroenteropancreatic neuroendocrine tumors undergoing [177Lu]Lu-DOTA-TATE therapy.","authors":"Felix L Herr, Christian Dascalescu, Ricarda Ebner, Moritz L Schnitzer, Matthias P Fabritius, Christine Schmid-Tannwald, Mathias J Zacherl, Vera Wenter, Lena M Unterrainer, Matthias Brendel, Adrien Holzgreve, Rudolf A Werner, Christoph J Auernhammer, Christine Spitzweg, Thomas Knösel, Tanja Burkard, Jens Ricke, Maurice M Heimer, Gabriel T Sheikh, Clemens C Cyran","doi":"10.7150/thno.112588","DOIUrl":"10.7150/thno.112588","url":null,"abstract":"<p><p>Integrated biomarkers that predict survival in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NET) receiving peptide receptor radionuclide therapy (PRRT) are still limited. This study aims to identify predictors of progression-free survival (PFS) in patients with GEP-NET undergoing two cycles of PRRT. <b>Methods:</b> This single-center retrospective study included 178 patients with GEP-NET (G1 and G2) who received at least two consecutive cycles of PRRT with [177Lu]Lu-DOTA-TATE and underwent somatostatin receptor (SSTR)-PET/CT before and after therapy. At baseline, Krenning score (KS) > 2, clinical, pathological and laboratory parameters were collected and correlated to PFS. Survival predictors were analyzed using univariate and multivariate models. For goodness-of-fit analysis, the Akaike information criterion and Harrell concordance index were determined. To determine the impact on the regression model the Wald-Test was performed. <b>Results:</b> In univariate analysis, KS 3 (vs. KS 4; HR, 2.02; 95% CI, 1.27-3.22; p = 0.012), Ki-67 > 5 % (HR, 2.00; 95% CI, 1.31-3.04; p = 0.008), CgA > 200 ng/mL (HR, 1.77; 95% CI, 1.14-2.76; p = 0.027) and NSE > 35 ng/mL (HR, 2.37; 95% CI, 1.44-3.89; p < 0.008) were significantly associated with shorter PFS, with CgA providing the highest C-index (0.6). In multivariate analysis , KS 3 (vs. KS 4; HR, 1.94; 95% CI, 1.17-3.21; p = 0.01), CgA > 200 ng/mL (HR, 1.76; CI, 1.08-2.87; p = 0.024), NSE > 35 ng/mL (HR, 1.98; 95% CI, 1.17-3.36; p = 0.011), and Ki-67 > 5 % (HR, 1.89; 95% CI, 1.18-3.02; p = 0.008) were significantly associated with reduced PFS. Including KS into multivariate analysis significantly improved the Cox regression model performance, as shown by a reduction in Akaike Information Criterion (592/596) and an increase in concordance index (0.66/0.65). The Wald test for individual variables supported the significance of both Ki-67 (7.1) and KS (6.7) as independent predictors of PFS. <b>Conclusions:</b> NSE, CgA, KS and Ki-67 emerged as independent predictors of PFS in GEP-NET patients scheduled for two cycles of PRRT, thereby emphasizing the importance of integrated diagnostics including in- and ex-vivo biomarkers to identify high-risk individuals prone to disease progression.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 13","pages":"6444-6453"},"PeriodicalIF":12.4,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12160013/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302863","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":"GPA33-pretargeted radioimmunotherapy with mono- and bivalent DOTA-based Lu-177-labeled radiohaptens in a mouse orthotopic liver xenograft model of metastatic human colorectal cancer.","authors":"Alexandre B Le Roux, Edward K Fung, Sang Gyu Lee, Sebastien Monette, Hong Xu, Hong-Fen Guo, Guangbin Yang, Ouathek Ouerfelli, Achim Jungbluth, Heiko Schöder, Steven M Larson, Nai-Kong V Cheung, Sarah M Cheal, Darren R Veach","doi":"10.7150/thno.107209","DOIUrl":"10.7150/thno.107209","url":null,"abstract":"&lt;p&gt;&lt;p&gt;&lt;b&gt;Rationale:&lt;/b&gt; Pretargeted radioimmunotherapy (PRIT), which combines systemic antibody-based targeting with ionizing radiation, is promising for treating liver metastases in patients with colorectal cancer (CRC). Previously, we established a three-step DOTA-PRIT regimen to deliver DOTA radiometal payloads to CRC using an anti-tumor/anti-DOTA bispecific antibody (BsAb) targeting cell surface glycoprotein A33 (GPA33), a tumor antigen target expressed on over 95% of primary and metastatic CRC; a clearing agent; and a monovalent &lt;sup&gt;177&lt;/sup&gt;Lu radiohapten called [&lt;sup&gt;177&lt;/sup&gt;Lu]Lu-ABD. More recently, we developed a bivalent &lt;sup&gt;177&lt;/sup&gt;Lu radiohapten called [&lt;sup&gt;177&lt;/sup&gt;Lu]Lu-Gemini to enhance tumor uptake and radiohapten retention. Here, we aimed to compare the efficacy and safety of bivalent vs. monovalent three-step DOTA-PRIT regimens in orthotopic CRC liver metastasis models, to mimic a clinical path forward. &lt;b&gt;Methods:&lt;/b&gt; We established two orthotopic CRC liver metastasis models by inoculating either SW1222-luc (GPA33&lt;sup&gt;high&lt;/sup&gt;) or LoVo (GPA33&lt;sup&gt;low&lt;/sup&gt;) human CRC cells in athymic nude mice under ultrasonographic guidance. Tumor targeting efficacy and dosimetry of the radiohaptens were compared using &lt;i&gt;ex vivo&lt;/i&gt; biodistribution studies, SPECT/CT, and quantitative autoradiography. We also performed a DOTA-PRIT experiment to compare the efficacy and safety profiles of bivalent (single-cycle [&lt;sup&gt;177&lt;/sup&gt;Lu]Lu-Gemini, 48 h pretargeting interval) vs. monovalent (multicycle [&lt;sup&gt;177&lt;/sup&gt;Lu]Lu-ABD, 24 h pretargeting interval) three-step DOTA-PRIT regimens, each designed to deliver comparable total radiation doses to tumors (around 50 Gy). &lt;b&gt;Results:&lt;/b&gt; Both radiohaptens demonstrated efficient SW1222-luc tumor targeting, with [&lt;sup&gt;177&lt;/sup&gt;Lu]Lu-Gemini showing superior targeting and tumor activity retention compared with [&lt;sup&gt;177&lt;/sup&gt;Lu]Lu-ABD. In LoVo tumors, [&lt;sup&gt;177&lt;/sup&gt;Lu]Lu-Gemini showed superior targeting, while [&lt;sup&gt;177&lt;/sup&gt;Lu]Lu-ABD showed negligible targeting. Dosimetry estimates revealed higher SW1222-luc tumor mean absorbed doses for [&lt;sup&gt;177&lt;/sup&gt;Lu]Lu-Gemini (119.88 cGy/MBq, 48 h pretargeting interval) compared with [&lt;sup&gt;177&lt;/sup&gt;Lu]Lu-ABD (32.88 cGy/MBq, 24 h pretargeting interval), with more favorable blood and kidney therapeutic indices (50 and 9 for [&lt;sup&gt;177&lt;/sup&gt;Lu]Lu-Gemini, and 15 and 5 for [&lt;sup&gt;177&lt;/sup&gt;Lu]Lu-ABD, respectively). In the DOTA-PRIT experiment, both monovalent (injected activity: 3 × 44.4 MBq, 133.2 MBq total) and bivalent (injected activity: 44.4 MBq total) radiohapten regimens increased the median survival of treated mice compared with controls: 71 days for [&lt;sup&gt;177&lt;/sup&gt;Lu]Lu-ABD-treated mice, 81 days for [&lt;sup&gt;177&lt;/sup&gt;Lu]Lu-Gemini-treated mice, and 18 days for controls, without a statistical difference between treatment groups. Treatments were well tolerated, without significant weight loss or hematologic changes. Radiation-induced injuries were not identified histo","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 13","pages":"6274-6289"},"PeriodicalIF":12.4,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12159840/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302874","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":"Loss of <i>SLC25A20</i> in Pancreatic Adenocarcinoma Reversed the Tumor-Promoting Effects of a High-Fat Diet.","authors":"Sang Myung Woo, Ho Lee, Joon Hee Kang, Mingyu Kang, Wonyoung Choi, Sung Hoon Sim, Jung Won Chun, Nayoung Han, Kyung-Hee Kim, Woojin Ham, Woosol Hong, Chaeyoung Kim, Jeong Hwan Park, Dawool Han, Jong In Yook, Woo Jin Lee, Soo-Youl Kim","doi":"10.7150/thno.114912","DOIUrl":"10.7150/thno.114912","url":null,"abstract":"<p><p><b>Rationale:</b> Although it is known that High-fat diet (HFD) promotes the development of pancreatic ductal adenocarcinoma (PDAC), no direct link between HFD and cancer has been identified. Previously, we showed that ATP production by cancer cells depends on fatty acid oxidation (FAO); therefore, we hypothesized that blocking FAO may prevent HFD-induced promotion of PDAC growth. <b>Methods:</b> To determine whether FAO is increased in PDAC patients, we analyzed a tissue microarray by immunohistochemical staining to detect carnitine palmitoyl transferase I. To block FAO, <i>SLC25A20</i> (carnitine-acylcarnitine carrier) was knocked down in cancer cells, which was implanted for xenograft in mice and treated with a high-fat diet (HFD, 60% fat). To compare cancer development including survival rates, and histopathological differences were analyzed by crossbreeding of KPC mice (<i>Kras^G12D/+; Trp53^R172H/+; Pdx1-Cre</i>) with KPC/<i>Slc25a20^+/-</i> mice. <b>Results:</b> <i>SLC25A20</i> knockdown in cancer cells reduced ATP production and inhibited cell growth. Proteome analysis revealed that <i>SLC25A20</i> knockdown reduced cancer cell growth significantly due to inactivation of mTOR via decreased ATP production, ultimately leading to cell death. The median survival time of KPC/<i>Slc25a20^+/-</i> tumor-bearing mice was 3.1 weeks longer than that of KPC tumor-bearing mice. In mice fed an HFD, the growth of xenografts derived from <i>SLC25A20</i> knockdown PDAC cells was 65-95% lower than that of xenografts derived from control cells. <b>Conclusion:</b> Blocking FAO by <i>SLC25A20</i> knockdown reversed HFD-induced promotion of PDAC growth.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 13","pages":"6516-6533"},"PeriodicalIF":12.4,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12160018/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302885","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":"An AIM2 inflammasome biomimetic mineralization inhibitor for vascular dementia therapy.","authors":"Yueqi Zhang, Lixian Jiang, Rongrong Wu, Wei Gao, Xiaojie Zhang, Lan Liu, Yaxuan Zhang, Jin Lu, Yuanyi Zheng, Xiaojun Cai, Jianliang Fu","doi":"10.7150/thno.110389","DOIUrl":"10.7150/thno.110389","url":null,"abstract":"<p><p><b>Rationale:</b> Absent in melanoma 2 (AIM2) inflammasome-mediated effector plays critical roles in multiple disease pathologies. While nanotechnology has revolutionized therapeutic development through novel approaches, the potential regulatory effects of nanoparticles on AIM2 inflammasome activity remain unexplored. Here, guided by clinical patient data and computational modeling, we developed an AIM2 inflammasome-targeting biomimetic mineralization inhibitor for vascular dementia (VaD) therapy. <b>Methods:</b> GEO datasets were analyzed to compare AIM2 inflammasome component expression in VaD patient brains versus controls. Molecular dynamics simulations identified high-affinity binding between manganese ferrocyanide and the AIM2 protein. We synthesized hollow manganese Prussian blue nanoparticles (HMPB) via biomineralization and functionalized them with M2 macrophage-derived extracellular vesicles (M2exo@HMPB). Therapeutic efficacy was evaluated in a VaD rat model through intravenous and intracerebroventricular administration, employing behavioral assessments, histopathological analysis, and inflammatory cytokine profiling. AIM2 inflammasome assembly and pyroptosis were investigated through protein immunoblotting, scanning electron microscopy/transmission electron microscopy (SEM/TEM) imaging of microglial cells, and primary microglia cultures under hypoxic-hypoglycemic conditions. <b>Results:</b> Gene expression analysis demonstrated significantly elevated levels of AIM2 inflammasome components in VaD patients compared to normal controls. Molecular dynamics simulations revealed effective binding of manganese ferrocyanide to AIM2. M2exo@HMPB targeted central inflamed sites and were ultimately phagocytosed by microglia. In an <i>in vitro</i> sustained hypoxic-hypoglycemic model, M2exo@HMPB inhibited AIM2 inflammasome assembly and pyroptosis in primary microglia, thereby reducing IL-18/IL-1β release and promoting neuronal survival. In VaD rat models, M2exo@HMPB alleviated neuronal loss and white matter lesions while improving learning and executive functions. Additionally, M2exo@HMPB demonstrated favorable <i>in vivo</i> biosafety. <b>Conclusions</b>: Integrating clinical bioinformatics with computational drug design, this study establishes a translational paradigm for nanomaterial development. M2exo@HMPB serves not only as an AIM2 inflammasome-targeting biomimetic mineralization inhibitor for VaD therapy but also provides new insights for treating AIM2-mediated cell death pathologies.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 13","pages":"6347-6368"},"PeriodicalIF":12.4,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12159838/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302853","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":"Precision treatment of ventilator-induced lung injury through alveolar epithelial cell targeted lipid nanoparticle delivery.","authors":"Ning Ding, Hui Xiao, Huiqing Li, Zengzhen Zhang, Junke Ge","doi":"10.7150/thno.111200","DOIUrl":"10.7150/thno.111200","url":null,"abstract":"<p><p><b>Rationale:</b> Biotrauma characterized by the release of inflammatory cytokines is a key pathological basis of ventilator-induced lung injury (VILI). Small interfering RNA (siRNA) can effectively reduce the release of inflammatory cytokines by inhibiting corresponding inflammatory pathways but may also affect innate immune responses. Therefore, it is promising to target ventilation-induced cytokine production without impairing lung innate immunity. <b>Methods:</b> We developed a novel approach to identify peptide targeting activated alveolar epithelial cells (AECs) in VILI mice by incorporating <i>in vivo</i> phage display, high-throughput sequencing, and bioinformatics analysis, and identified a pentapeptide (SPFPT) with high affinity for activated AECs. The SPFPT peptide was then conjugated into lipid nanoparticles (LNPs) to co-deliver importin-7 siRNA (siImp7) and polydatin (PD). The delivery efficiency and biological activity of SPFPT@siImp7/PD-LNP were assessed by <i>in vitro</i> and <i>in vivo</i> experiments. <b>Results:</b> SPFPT@siImp7/PD-LNP demonstrated significant enhancement in targeting mechanical stretch-activated AECs both <i>in vitro</i> and <i>in vivo</i>. Intratracheal administration of SPFPT@siImp7/PD-LNP effectively inhibited the release of inflammatory cytokines and ameliorated VILI and associated distal organ injury by simultaneously suppressing p38 and NF-κB pathways. Importantly, SPFPT@siImp7/PD-LNP did not interfere with lung innate immunity. <b>Conclusions:</b> The results suggest that the nanocomplex of SPFPT@siImp7/PD-LNP is promising to be highly effective in the precise treatment of VILI.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 13","pages":"6534-6552"},"PeriodicalIF":12.4,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12160035/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302819","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":"Development of a Janus nanofibrous patch with antibacterial and anti-oxidative properties for urethral regeneration.","authors":"Wang Wang, Zesheng Chen, Ruoyu Li, Zhijun Zhou, Guanyi Wang, Xinjun Su, Weikang Hu, Zijian Wang, Xingyuan Xiao, Bing Li","doi":"10.7150/thno.112435","DOIUrl":"10.7150/thno.112435","url":null,"abstract":"<p><p><b>Background:</b> Urethral injury is the primary cause of urinary tract stenosis and hydronephrosis. Limited by the common drawbacks of autografts, the clinical treatment of urethral injury remains challenging. In recent years, biocompatible and biodegradable biomaterials (BBBs) are emerging as a potential substitute for autografts to upgrade the research paradigms of regenerative medicine. However, ideal BBBs for urethral regeneration have rarely been reported. <b>Methods:</b> A Janus nanofibrous PC/SMC patch composed of the outer layer of PLLA/CRRI-3 nanofibers and the inner layer of SF/MCe heterojunction nanofibers were first fabricated. Its antibacterial and antioxidant properties were assessed. After passing biosafety evaluation, the patch's efficacy in repairing urethral defects was evaluated using a rabbit model, with repair outcomes analyzed via histological staining. <b>Results:</b> PC/SMC patch not only inhibits bacterial proliferation and survival via the release of the antibacterial peptide CRRI-3, but it also relieves oxidation stress and promotes tissue regeneration by the nanozyme-like activities of the MCe heterojunction. The biocompatibility of PC/SMC patch has met the general requirements for Class-III medical devices. The application <i>in vivo</i> was evaluated using a urethral injury model of rabbits. The results showed that PC/SMC patch could improve urethral regeneration and prevent urethral stricture via multiple mechanisms, including promoting re-epithelialization, cell proliferation and M2 macrophage polarization, and inhibiting of fibrosis and scar formation. <b>Conclusion:</b> The PC/SMC nanofibrous patch has good biocompatibility and antibacterial properties, and can effectively promote the regeneration and repair of urethral tissue.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 13","pages":"6428-6443"},"PeriodicalIF":12.4,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12160026/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302869","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":"KLK8/HGF/Met signaling pathway mediates diabetes-associated hippocampal neuroinflammation in male mice.","authors":"Dan-Hong Xu, Xiao-Yong Zhang, Shi-Yu Liu, Juan Wei, Jun-Hui Zhan, Jian-Kui Du, Yu-Jian Liu, Xiao-Yan Zhu","doi":"10.7150/thno.109513","DOIUrl":"10.7150/thno.109513","url":null,"abstract":"&lt;p&gt;&lt;p&gt;&lt;b&gt;Rationale:&lt;/b&gt; Neuroinflammation plays a critical role in the pathogenesis of diabetes-associated depression. Tissue kallikrein-related peptidase 8 (KLK8), a secreted serine protease, has been implicated in the pathogenesis of depression- and anxiety-related behaviors across various etiologies, however the underlying mechanisms remain largely unexplored. This study elucidates a novel mechanism by which KLK8 upregulation contributes to diabetes-induced microglial activation and neuroinflammation in the hippocampus through modulating the hepatocyte growth factor (HGF)/Met signaling pathway. &lt;b&gt;Methods and Results:&lt;/b&gt; Streptozotocin (STZ)-induced diabetic mice exhibited increased KLK8 expression in the hippocampus, an effect that was mitigated in KLK8-deficient or aerobic running-exercised mice. KLK8 deficiency significantly reduced depression-like behaviors, microglial activation, and neuroinflammation in diabetic mice. In BV2 mouse microglial cells, adenovirus-mediated overexpression of KLK8 (Ad-KLK8) was sufficient to induce microglial activation. Co-immunoprecipitation (Co-IP) coupled with mass spectrometry revealed that CD44 might interact with KLK8. KLK8 overexpression decreased CD44 levels in microglial cells. However, the CD44 activator Angstrom6 further exacerbated KLK8-induced microglial activation. Conversely, transcriptional profiling of KLK8-overexpressing microglial cells and subsequent validation demonstrated that the Met/Src/Btk/NF-κB signaling pathway played a central role in mediating the stimulatory effects of KLK8 on microglial activation in both Ad-KLK8-treated BV2 cells and human microglial cell line HMC3 cells stably transfected with KLK8 lentivirus (Lv-KLK8). The Met receptor is activated upon binding to its ligand HGF, which exists as an inactive precursor (pro-HGF). Our findings showed that KLK8 cleaved pro-HGF, promoting HGF release and subsequently activating the Met/Src/Btk/NF-κB signaling pathway in microglial cells. High glucose conditions increased KLK8 expression and enhanced HGF release, thereby stimulating the Met/Src/Btk/NF-κB signaling pathway and microglial activation in a KLK8-dependent manner. Systemic administration of a Met inhibitor inactivated the Met/Src/Btk/NF-κB pathway, reducing depression-like behaviors, microglial activation, and neuroinflammation in STZ-induced diabetic mice. Both Met inhibitor and KLK8 deficiency enhanced hippocampal neuroplasticity in STZ-induced diabetic mice. Finally, we demonstrated that running exercise reversed KLK8 upregulation and inactivated Met/Src/Btk/NF-κB signaling pathways, thereby attenuating neuroinflammation, improving neuroplasticity, and alleviating depression-like behaviors in STZ-induced diabetic mice. &lt;b&gt;Conclusions:&lt;/b&gt; This study provides evidence that the KLK8/HGF/Met signaling pathway mediates diabetes-associated hippocampal neuroinflammation and depression-like behaviors, highlighting the therapeutic potential of targeting this pathway in diabet","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 13","pages":"6290-6312"},"PeriodicalIF":12.4,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12159841/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302882","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":"Limitations of the radiotheranostic concept in neuroendocrine tumors due to lineage-dependent somatostatin receptor expression on hematopoietic stem and progenitor cells.","authors":"Nghia Nguyen, Yu Min, Jennifer Rivière, Mark van der Garde, Sukhen Ghosh, Laura M Bartos, Matthias Brendel, Florian Bassermann, Ali Azhdarinia, Wolfgang A Weber, Katharina S Götze, Susanne Kossatz","doi":"10.7150/thno.113354","DOIUrl":"10.7150/thno.113354","url":null,"abstract":"<p><p><b>Rationale:</b> Radiopharmaceutical therapy (RPT) has become an effective treatment option for neuroendocrine tumors (NETs) and castration-resistant prostate cancer and is in clinical development for many indications. One of the major advantages of theranostic RPT is that the distribution of radiopharmaceuticals in the human body can be imaged, and radiation doses to the patient's organs can be calculated. However, accurate dosimetry may be fundamentally limited by microscopic heterogeneity of radiopharmaceutical distribution. <b>Methods:</b> We developed fluorescent analogs of somatostatin-receptor-subtype 2 (SSTR2) targeting Lutetium-177 labeled radiopharmaceuticals that are clinically used in patients with NETs and studied their uptake by hematopoietic stem and progenitor cells (HSPC) using flow cytometry and microscopy. <b>Results:</b> Hematopoietic stem cells (HSCs) and multipotent progenitor cells (MPPs) showed high and specific SSTR2-ligand uptake, which was at similar levels as NET cells. Furthermore, they displayed a several-fold higher uptake of SSTR2-antagonists than of SSTR2-agonists. HSPC treatment with a 177Lu-labeled antagonist and agonist showed a stronger reduction of HSC proliferation by the antagonist. Due to the scarcity of HSCs and MPPs, their contribution to total bone marrow uptake of SSTR2-radiopharmaceuticals is negligible in imaging-based dosimetry. This likely explains why SSTR2-antagonists caused pancytopenia in clinical trials despite safe dosimetry estimates. <b>Conclusion:</b> Target expression heterogeneity can lead to underestimation of radiopharmaceutical toxicity and should be considered when designing clinical trials for new radiopharmaceuticals. The implications of our findings go beyond SSTR2-targeted radiopharmaceuticals and suggest more generally that first-in-human studies should not only be guided by radiation dosimetry but should also include careful escalation of the administered therapeutic activity. Our multimodal ligand design is modular and can be applied to other peptide or protein-based radiopharmaceuticals to study cellular distribution and potential bone marrow uptake prior to clinical testing.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 13","pages":"6497-6515"},"PeriodicalIF":12.4,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12160025/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302884","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":"Mechanotransduction-enhanced bioconstructs fabricated using a bioink comprising collagen and omega-3 fatty acids for gingival tissue regeneration.","authors":"GaEun Heo, Hoon Noh, Dogeon Yoon, SooJung Chae, Hanjun Hwangbo, Ji Hye Park, Won Hee Lim, WonJin Kim, GeunHyung Kim","doi":"10.7150/thno.114503","DOIUrl":"10.7150/thno.114503","url":null,"abstract":"<p><p><b>Rationale:</b> Tissue engineering through three-dimensional (3D) bioprinting has emerged as a highly promising strategy for creating custom-designed 3D bioconstructs that closely mimic native tissue architecture. However, ongoing advancements in bioink formulation and bioprinting processes are required to achieve precise replication of target tissues. In particular, effective vascularization and extracellular remodeling are essential for successful gingival tissue regeneration. <b>Methods:</b> To achieve this, we propose a cell-laden collagen bioink formulation containing omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), for gingival tissue regeneration. To enhance the mechanotransduction of human gingival fibroblasts (hGFs) encapsulated in the bioink, we employed a shear-induced bioprinting process to activate key signaling pathways, including mechanosensitive channels, which are involved in gingival tissue regeneration. <b>Results:</b> Bioprinted cell constructs subjected to both biochemical and biophysical cues exhibited promising gene expression profiles related to collagen production and angiogenesis, demonstrating the potential of integrating bioprinting with mechanical and biochemical stimulation for gingival tissue engineering. Furthermore, when hGF-laden bioconstructs containing EPA/DHA were implanted subcutaneously into mice, the formation of blood vessel-like structures was clearly observed at four weeks post-transplantation. <b>Conclusion:</b> These results suggest that the engineered bioconstruct, incorporating EPA/DHA-assisted bioinks and mechanical stimulation, may offer a promising strategy for gingival tissue regeneration and the development of a 3D biomimetic model within an oral organ-on-a-chip system.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 13","pages":"6476-6496"},"PeriodicalIF":12.4,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12160015/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302887","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":"BCAA catabolism targeted therapy for heart failure with preserved ejection fraction.","authors":"Meng Wang, Zhao Liu, Shuxun Ren, Jinyun Zhu, Norihiko Morisawa, Geok Lin Chua, Xuewen Zhang, Yun Ka Wong, Liping Su, Ming Xiang Wong, Jieping Yang, Marc Titze Jens, Zhaoping Li, Haipeng Sun, Yibin Wang, Christoph D Raul, Sanjiv J Shah, Chen Gao, Yunxia Liu","doi":"10.7150/thno.105894","DOIUrl":"10.7150/thno.105894","url":null,"abstract":"<p><p><b>Rationale:</b> Heart failure with preserved ejection fraction (HFpEF) is a major unmet medical need with limited effective treatments. A significant contributing factor to HFpEF, a multifactorial disease, is underlying metabolic dysfunction. While much of the prior research has been on glucose and fatty acid metabolic defects in the pathogenesis of HFpEF, other metabolic activities remain under investigated. <b>Methods:</b> System-based metabolomics and targeted mass spectrometry were employed to analyze serum and tissue samples from a deep-phenotyped human HFpEF cohort. A preclinical mouse model of HFpEF was developed by combined administration of a high-fat diet (HFD) and the nitric oxide (NO) synthase inhibitor N[w]-nitro-l-arginine methyl ester (L-NAME). The branched-chain amino acid (BCAA) catabolic activities were enhanced by genetic inactivation of branched-chain ketoacid-dehydrogenase kinase (BCKDK) or treatment with BT2 (3,6-dichlorobenzo[b]thiophene-2-carboxylic acid), a highly selective inhibitor of BCKDK. Cardiac function, myocardial remodeling and insulin signaling in the left ventricle were assessed across all experimental cohorts. <b>Results:</b> The systems-based metabolomics analysis of the deep-phenotyped HFpEF and non-HFpEF patients revealed that abnormal circulating BCAA levels were significantly associated with adverse outcomes. In the rodent model of HFpEF, significant impairment of BCAA catabolic activities in the heart and abnormal circulating BCAA levels were also observed. In adult mice, inducible knockout of BCKDK, the rate-limiting negative regulator of BCAA catabolic flux, markedly augmented BCAA catabolic activities. Compared with the controls, BCKDK inactivation blunted diastolic dysfunction, cardiac hypertrophy and myocardial remodeling in response to chronic treatment with HFD/L-NAME. This functional amelioration was associated with improved insulin signaling in the myocardium and reduced S-nitrosylation of cardiac proteins, without any impact on systemic blood pressure. Finally, pharmacological inhibition of BCKDK in HFpEF mice significantly reversed the diastolic dysfunction and cardiac hypertrophy associated with HFpEF. <b>Conclusions:</b> Our study provides the first proof-of-concept evidence that global catabolic impairment of BCAAs is an important pathogenic contributor and metabolic signature of HFpEF and restoring BCAA catabolic flux could be an efficacious therapeutic strategy for HFpEF.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 13","pages":"6257-6273"},"PeriodicalIF":12.4,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12159833/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302864","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}