tbuckley/cabot-search huggingface dataset:
The inter-organelle cross-talk finely orchestrated in the amyloidogenic processing of amyloid precursor protein in dendritic arborization neurons of <i>Drosophila</i>
Authors: Guo Cheng, Jin Chang, Shanshan Ke, Zimin Dai, Deyong Gong, Hui Gong, Wei Zhou
Journal: Theranostics (2025)

Background: Organelles in neuronal dendrites facilitate local metabolic processes and energy supply, crucial for dendrite development and neurodegenerative diseases. The distinct functions of dendritic organelles have been well studied, however, their crosstalk under physiological and pathological contexts remains elusive. We aimed to establish an in vivo model system of contacts between multi-organelles for investigating the modulation of inter-organelle crosstalk in Alzheimer's disease (AD). Methods: A dendrite model of organelle contacts was developed in Drosophila neurons using a set of proximity-driven probes and four-color Airyscan super-resolution imaging. The systematic modulations among multiple contact sites (CSs) between organelles were examined by manipulating CS tethers and vesicular transporters. Finally, perturbations of these CSs and the dendrite structure in the amyloidogenic processing of amyloid precursor protein (APP) were evaluated by introducing three stages of the processing in this model system. Results: A dynamic network, interconnected via CSs and organized with multi-organelle contacts, was presented among Golgi outposts, the endoplasmic reticulum, lysosomes, and mitochondria (GELM). The CS modulations were found to encompass both their density and motility. Notably, multi-CSs participated in complementary modulations spanning across different cellular pathways. Furthermore, the CS network was revealed to be progressively disturbed in APP amyloidogenic processing, with upregulations in density and motility extending from single- to multi-CSs. These CS perturbations, along with defects in dendrite structural plasticity, could be partially rescued by knocking down Miro. Conclusion: The elucidation of CS modulation modes in the GELM network model reveals a cascaded dysregulation of organelle crosstalk during APP amyloidogenic processing. It expands the mechanisms of inter-organelle communication and provides novel insights into neurodegeneration in AD pathology.
FBXW7/GSK3β-mediated proline-rich 11 degradation promotes oxidative DNA damage and inhibits tumor progression in renal cell carcinoma
Authors: Siming Chen, Kangping Xiong, Jianmin Liu, Shijie Yao, Mingxing Li, Jingtian Yu, Gang Wang, Sheng Tu, Wan Jin, Jiageng Shi, Yu Xiao, Yi Zhang, Kaiyu Qian, Lingao Ju, Xinghuan Wang
Journal: Theranostics (2025)

Rationale: Renal cell carcinoma (RCC) is a highly malignant and common urological tumor. In our previous study, we reported the upregulation of PRR11 in RCC, emphasizing its important role in cell cycle regulation and apoptosis. In this follow-up study, we aim to further investigate the carcinogenic mechanism of PRR11. Methods: Immunoprecipitation-mass spectrometry (IP-MS), ubiquitination assays, and in vitro phosphorylation assays were used to investigate the phosphorylation and ubiquitination-mediated degradation of PRR11 by FBXW7 and GSK3β. RNA-seq analysis of PRR11 knockdown RCC cells and cellular functional assays, including flow cytometry and comet assays, were performed to explore downstream signaling pathways and regulatory functions. Mouse subcutaneous tumor, tail vein lung metastasis, and popliteal lymph node metastasis models were established to validate PRR11's role in vivo. Results: Our results reveal that GSK3β recognizes and phosphorylates the CDC4 phosphodegron (CPD) consensus motif of PRR11, enabling FBXW7 to bind to PRR11 and catalyze its K48-linked ubiquitination and degradation. Moreover, PRR11 activates AKT signaling, which inhibits GSK3β activity. This inhibition prevents the phosphorylation of CPD motifs on PRR11, thereby obstructing FBXW7-mediated ubiquitination and degradation. The interaction between PRR11 and AKT creates a positive feedback loop that increases the level of both proteins, which ultimately accelerates RCC progression by inhibiting oxidative DNA damage. Conclusion: The FBXW7/GSK3β-PRR11-AKT axis plays a pivotal role in the development of RCC by regulating oxidative DNA damage. Targeting PRR11 may be a potential therapeutic strategy for RCC.
Supercharging CAR-T cells through transcriptional and epigenetic armoring
Authors: Diyuan Qin, Yanna Lei, Pei Shu, Yugu Zhang, Yuin-Han Loh, Yongsheng Wang, Qijing Li
Journal: Theranostics (2025)

Inspired by the remarkable success of CAR-T therapy in hematologic malignancies, research is increasingly focused on adapting this treatment for solid tumors. However, CAR-T efficacy remains limited due to its exhaustion and shortened persistence. Transcription factors and epigenetic modifications play pivotal roles in modulating T cell differentiation and functionality, which have been leveraged in numerous strategies to promote the formation of long-lasting memory cells with stem-like properties and supercharging CAR-T performance. This review highlights pivotal transcriptional factors, such as c-Jun and FOXO1, which enhance and sustain T cell effector function, diminishes exhaustion, and epigenetic regulators like TET2 and DNMT3A, whose knockout promotes memory T subsets formation. We explore their interconnections, downstream targets, biological impacts, and the potential application risks of certain candidates, providing a comprehensive theoretical framework for supercharging CAR-T therapies through transcriptional and epigenetic interventions.
The allogenic non-proteinogenic amino acid BMAA-based vaccine breaks up the immune tolerance against colorectal cancer
Authors: Baorui Tian, Shijian Wang, Jixuan Ding, Weiao Qu, Chen Zhang, Fangqun Luan, Nan Wang, Yigong Hou, Mengying Suo, Huimin Liu, Yanan Chen, Yanhua Liu, Jie Yan, Jianbo Zhang, Jia Li, Longlong Wang, Yi Shi, Rong Xiang
Journal: Theranostics (2025)

The fundamental issue in immunotherapy is the lack of tumor-specific antigens in most types of tumors, leading to immune tolerance. For approximately 85% of patients with microsatellite stable (MSS) colorectal cancer (CRC), the absence of tumor neoantigens results in poor immunotherapy efficacy. Our previous study demonstrated that the misincorporation of non-proteinogenic proline (Pro) analog azetidine-2-carboxylic acid (AZE) could generate mutated proteins that significantly enhance tumor cell antigenicity and anti-tumor immune responses. Methods: To activate more specific anti-tumor immune responses with fewer side effects, we utilized the non-proteinogenic serine (Ser) analog β-N-methylamino-L-alanine (BMAA), which can be misincorporated into proteins as a Ser substitute by seryl tRNA synthetase at an appropriate rate. BMAA misincorporated neoantigens were detected using mass spectrometry (MS), and cancer cell-enriched peptides with high antigenicity were selected in a murine CRC model for the preparation of BMAA-based self-assembling nanoparticles (SAN). Single-cell sequencing was performed to analyze immune responses induced by SAN vaccination combined with a toll-like receptor 7 agonist (TLRa) adjuvant and BMAA treatment. Results: SAN-TLRa vaccination with BMAA treatment induced an anti-tumor immune microenvironment. This combination stimulated the generation of specific CD8+ T cells and IgG targeting BMAA misincorporated neoepitopes, ultimately promoting immune activation, tumor suppression, and prolonged survival in the CRC murine model. Additionally, BMAA combined with SAN vaccine significantly enhanced the efficacy of the immune checkpoint inhibitor anti-PD-1 antibody. Conclusion: Our findings provide a promising strategy for artificially introducing neoantigens using BMAA, which can break immune tolerance without disrupting systemic immune balance. This approach offers novel avenues for CRC immunotherapy.
NAE1-mediated neddylation coordinates ubiquitination regulation of meiotic recombination during spermatogenesis
Authors: Yu Xi, Chenjia Gong, Zhe Zhang, Feiyin Zhu, Ying Zhang, Yanlin Tang, Liying Yan, Hui Jiang, Jie Qiao, Qiang Liu
Journal: Theranostics (2025)

Rationale: Meiotic homologous recombination is a critical event in gametogenesis, which is tightly regulated to ensure the generation of crossovers on homologous chromosomes. This process is crucial for ensuring the accurate segregation of genetic material and maintaining genetic diversity within species, ultimately contributing to reproductive success. Nevertheless, comprehensive mechanisms of post-translational modification (PTM) regulating homologous recombination during meiosis require further investigation. The aim of this study is to investigate the regulatory mechanisms and physiological functions of NAE1-mediated neddylation during meiosis of mammalian spermatogenesis and its consequential role in infertility. Methods: The dynamic localization of NAE1 at various sub-stages during spermatogenesis was determined using immunofluorescence staining and seminiferous tubule staging. We explore the role of NAE1-mediated neddylation by utilizing germ cell-specific Nae1-knockout mice. The impact on homologous synapsis and recombination during the meiosis prophase I were verified through chromosome spread fluorescence staining. We used 10 × Genomics single cell transcriptomics and ubiquitinomics to analysis the causes of spermatogenesis arrest and spermatogenic apoptosis. Results: NAE1 exhibited high nuclear expression within spermatocytes from the pachytene stage onwards. Nae1-SKO male mice showed a late-pachytene arrest in spermatocytes, resulting in infertility. In NAE1-deficient spermatocytes, there is an increase in apoptosis. Nae1 deletion led to double-strand break (DSB) repair failure with normal autosomes synapsis. From a mechanistic perspective, we verified excessive recombination intermediate stabilization and failed crossover formation, which ultimately resulted in impaired meiotic recombination. Further analysis showed that ubiquitination regulation coordinated with NAE1-mediated neddylation was implicated in meiotic recombination. Conclusion: NAE1-mediated neddylation regulates ubiquitination during meiosis and is involved in the stabilization of recombination proteins related to crossover differentiation. We provide cytological evidence for the neddylation-ubiquitination system (NUS) in mammalian meiotic recombination during spermatogenesis.
Artificial intelligence-enhanced retinal imaging as a biomarker for systemic diseases
Authors: Jinyuan Wang, Ya Xing Wang, Dian Zeng, Zhuoting Zhu, Dawei Li, Yuchen Liu, Bin Sheng, Andrzej Grzybowski, Tien Yin Wong
Journal: Theranostics (2025)

Retinal images provide a non-invasive and accessible means to directly visualize human blood vessels and nerve fibers. Growing studies have investigated the intricate microvascular and neural circuitry within the retina, its interactions with other systemic vascular and nervous systems, and the link between retinal biomarkers and various systemic diseases. Using the eye to study systemic health, based on these connections, has been given a term as oculomics. Advancements in artificial intelligence (AI) technologies, particularly deep learning, have further increased the potential impact of this study. Leveraging these technologies, retinal analysis has demonstrated potentials in detecting numerous diseases, including cardiovascular diseases, central nervous system diseases, chronic kidney diseases, metabolic diseases, endocrine disorders, and hepatobiliary diseases. AI-based retinal imaging, which incorporates established modalities such as digital color fundus photographs, optical coherence tomography (OCT) and OCT angiography, as well as emerging technologies like ultra-wide field imaging, shows great promises in predicting systemic diseases. This provides a valuable opportunity for systemic diseases screening, early detection, prediction, risk stratification, and personalized prognostication. As the AI and big data research field grows, with the mission of transforming healthcare, they also face numerous challenges and limitations both in data and technology. The application of natural language processing framework, large language model, and other generative AI techniques presents both opportunities and concerns that require careful consideration. In this review, we not only summarize key studies on AI-enhanced retinal imaging for predicting systemic diseases but also underscore the significance of these advancements in transforming healthcare. By highlighting the remarkable progress made thus far, we provide a comprehensive overview of state-of-the-art techniques and explore the opportunities and challenges in this rapidly evolving field. This review aims to serve as a valuable resource for researchers and clinicians, guiding future studies and fostering the integration of AI in clinical practice.
Perfluorocarbon nanoemulsions in drug delivery: design, development, and manufacturing
Authors: Riddhi Vichare, Jelena Janjic
Journal: Theranostics (2025)

Perfluorocarbons (PFCs) are formulated into kinetically stable nanoemulsions (NEs) having a droplet diameter less than 500 nm for biomedical applications. PFC NEs are developed for various applications, such as 19F magnetic resonance imaging tracers, ultrasound contrast agents, and oxygen carriers. They are an attractive platform for theranostic development, as PFC NEs can be designed to deliver a multitude of therapeutics, from small molecules to biologics. Although many reviews have been published on designing PFC NEs as imaging agents or oxygen carriers, there is no comprehensive review of the formulation strategies and manufacturing of PFC NEs as drug delivery platform. From a "formulator's perspective," the presented review addresses this gap as it describes the selection of formulation components such as the PFCs, surfactants, and hydrocarbon oils and provides an overview of manufacturing techniques. In this review, we will also identify potential shortcomings in the published literature on the manufacturing of PFC NEs. We will discuss the need for the implementing Quality by Design (QbD) approach in the manufacturing of PFC NEs to achieve scalability and necessary quality control for supporting both preclinical and clinical applications. Finally, we will review different surface-conjugation strategies for developing targeted PFC NEs. Overall, this article aims to increase understanding of PFC NEs designed for delivering drugs, including both small molecules and biologics.
Sex- and age-specific sensitivities of the endocannabinoid system in Alzheimer's disease revealed by PET imaging with [<sup>18</sup>F]FMPEP-<i>d</i><sub>2</sub> and [<sup>18</sup>F]MAGL-2102
Authors: Anna Pees, Christopher Daniel Morrone, Junchao Tong, Jian Rong, Tuo Shao, Darcy Wear, Steven H Liang, Wai Haung Yu, Neil Vasdev
Journal: Theranostics (2025)

The endocannabinoid system is a critical brain signaling pathway that is dysregulated in various brain disorders, including Alzheimer's disease (AD). Cannabinoid-targeted therapies and imaging approaches have gained increasing interest; however, the biological impact of the endocannabinoid system in disease needs further validation. We aimed to study changes in cannabinoid receptor 1 (CB1) and monoacylglycerol lipase (MAGL), components of endocannabinoid signaling and degradation, in a mouse model of AD by PET imaging. Methods: [18F]FMPEP-d 2 and [18F]MAGL-2102 were produced on a commercial radiosynthesis module. PET-CT images with both tracers were acquired in a knock-in mouse model of AD bearing mutated human amyloid precursor protein (AppNL-G-F ) at 3 ages, and compared to wild-type mice. Excised brains were used for in vitro autoradiography with [18F]FMPEP-d 2 and [18F]MAGL-2102, immunofluorescence, and western blotting. Male wild-type and 5xFAD mice were chronically treated with MAGL inhibitor JZL184 and imaged with [18F]MAGL-2102 two days after ending treatment. Results: PET imaging showed sex-, age- and genotype-dependent changes in CB1 and MAGL availability. At 4-months (early-stage β-amyloid pathology), female AppNL-G-F mice had lower CB1 availability, and MAGL availability was increased in male AppNL-G-F , compared to wild-types. At 8-months, no genotype differences in CB1 were observed, yet MAGL availability was reduced in AppNL-G-F frontal cortex, and male AppNL-G-F mice exhibited higher MAGL than transgenic females brain-wide. At 12-months (late-stage β-amyloid pathology), significantly lower uptake of [18F]FMPEP-d 2 was observed in AppNL-G-F compared to wild-type, with no changes in [18F]MAGL-2102 binding. AppNL-G-F plaque staging was confirmed by Thioflavin-S staining. Imaging findings were supplemented by autoradiography, immunofluorescence, and western blots. [18F]MAGL-2102 availability was responsive to target engagement of the MAGL inhibitor JZL184 in wild-type and 5xFAD mice. Conclusions: The present study showed dynamic age-, sex- and pathology-related changes in CB1 and MAGL availability from early-stage β-amyloid pathology, suggesting that the endocannabinoid system is a useful target for diagnostics and treatment of AD. Finally, these results highlight that endocannabinoid sex differences should be considered in diagnostics and drug development.
Coupling CRISPR-Cas and a personal glucose meter with an enzymatic reporter for portable detection of human papillomavirus in biological samples
Authors: Xuena Zhu, Shanshan Wang, Yuanyuan Xue, Xiaoyan Wang, Shaoqi Hu, Tingbo Liang, Wenjun Liu
Journal: Theranostics (2025)

Significant efforts and resources have been dedicated to developing CRISPR-Cas based point-of-care testing (POCT) and self-diagnosis methods for nucleic acid pathogens, aiming to complement the gold standard quantitative PCR tests, particularly in settings where centralized facilities, trained personnel, or resource-intensive equipment are unavailable. However, the reliance on stationary, high-cost readout machinery hinders their full deployment at the point of care. We aimed to develop a solid-phase invertase-labeled reporter (ILR) system that enables convenient readout of CRISPR-Cas reactions, facilitate HPV detection in a POCT-compatible manner. Methods: Through multiple chemical couplings, invertase is immobilized onto magnetic microbeads via a nucleic acid linker that responds to target nucleic acid-induced CRISPR-Cas activation. This activation releases active invertase, which then converts sucrose to glucose in proportion to the target's abundance. Enzymatic signal amplification by Cas12a/Cas13a and invertase compensates for the moderate sensitivity of personal glucose meters (PGMs). Results: When applied to human papillomavirus detection, the HPV18-targeted LAMP-Cas12a/ILR/PGM system can detect as few as 7 HPV18-positive HeLa cells out of 7,000, achieving 95.8% sensitivity and 100% specificity in cervical cell samples. Furthermore, minimal reagent adjustments allow for the rapid establishment of HPV16 and HPV52-targeted LAMP-Cas12a/ILR/PGM systems, offering satisfactory sensitivity, specificity, and cross-species detection. Conclusion: These findings demonstrate a highly efficient testing platform for a range of nucleic acid pathogens, suitable for both point-of-care and household use.
Astrocytic YAP protects the optic nerve and retina in an experimental autoimmune encephalomyelitis model through TGF-β signaling: Erratum
Authors: Qian Wu, Xuemeng Miao, Jingjing Zhang, Ludan Xiang, Xiuchun Li, Xiaomei Bao, Siyu Du, Mianxian Wang, Shuangda Miao, Yiren Fan, Wei Wang, Xingxing Xu, Xiya Shen, Danlu Yang, Xiwu Wang, Yuanyuan Fang, Lixin Hu, Xuyi Pan, Haoru Dong, Hui Wang, Ying Wang, Jia Li, Zhihui Huang
Journal: Theranostics (2025)

[This corrects the article DOI: 10.7150/thno.60031.].
Unveiling the potential of biomechanics in pioneering innovative strategies for cancer therapy
Authors: Xiaodong Wu, Weidong Fei, Tao Shen, Lei Ye, Chaoqun Li, Siran Chu, Mingqi Liu, Xiaodong Cheng, Jiale Qin
Journal: Theranostics (2025)

Mechanical force transmission is pivotal in tumor biology, profoundly affecting cancer cell behaviors such as proliferation, metastasis, and resistance to therapy. To explore novel biomechanical-based therapeutic strategies for cancer treatment, this paper deciphers the advances in biomechanical measurement approaches and the impact of biomechanical signals on fundamental oncological processes such as tumor microenvironment remodeling, angiogenesis, metastasis, and drug resistance. Then, the mechanisms of biomechanical signal transduction of tumor cells are demonstrated to identify novel targets for tumor therapy. Additionally, this study proposes a novel tumor treatment strategy, the biomechanical regulation tumor nanotherapeutics, including smart biomaterials designed to disturb mechanical signaling pathways and innovative nanodrugs that interfere transduction of biomechanical signals to improve tumor therapeutic outcomes. These methods mark a departure from conventional pharmacological therapies to novel strategies that utilize mechanical forces to impede tumor progression and enhance tumor responsiveness to treatment. In general, this review highlights the critical role of biomechanical signals in cancer biology from a holistic perspective and underscores the potential of biomechanical interventions as a transformative class of therapeutics. By integrating mechanobiology into the development of cancer treatments, this paper paves the way for more precise and effective strategies that leverage the inherent physical properties of the tumor microenvironment.
PBRM1 deficiency enhances PD1 immunotherapeutic sensitivity via chromosomal accessibility in colorectal cancer
Authors: Rui Li, Jie He, Chaoqun Liu, Zesheng Jiang, Jiasheng Qin, Kun Liang, Zhuocheng Ji, Liang Zhao
Journal: Theranostics (2025)

Rationale: Tumor cell epigenetics, especially chromosome accessibility, has been reported to be closely related to the tumor immune landscape and immunotherapy. However, the exact mechanism remains unknown. Methods: Whole-exome sequencing was used to analyze 13 colorectal tumor samples treated with PD1 immunotherapy. The assays for transposase-accessible chromatin using sequencing (ATAC-seq) and RNA sequencing were used to detect tumor cells' chromosome accessibility status and screen regulatory pathways. Results: Polybromo-1 (PBRM1) was one of the 12 genes with the highest frequency of somatic mutations associated with immunotherapy sensitivity. PBRM1/Pbrm1 deficiency in colorectal cancer promoted PD-1 immunotherapy sensitivity and chemotaxis of CD8+ T and NK cells in the microenvironment in vivo and in vitro. ATAC sequencing revealed that deletion of Pbrm1, a critical component of the SWI/SNF complex, increased chromosomal accessibility in tumor cells and triggered the release of cytokines, such as CCL5 and CXCL10, by activating the NF-κB signaling pathway. Application of ACBL1, a PROC inhibitor of PBRM1, in BALB/C mice or colorectal patient-derived tumor organoids (PDTOs) significantly promoted the sensitivity to PD1 antibody immunotherapy. Conclusions: Our study established that PBRM1/Pbrm1 deficiency was positively correlated with PD1 immunotherapeutic sensitivity in colorectal cancer. The underlying molecular mechanisms involved regulation of chromosome accessibility, activation of the NF-κB signaling pathway, and immune cell infiltration in the microenvironment. These findings identify potential molecular targets for enhancing immunotherapy for colorectal cancer.