tbuckley/cabot-search huggingface dataset:
Blockade of CD93 in pleural mesothelial cells fuels anti-lung tumor immune responses
Authors: Chengyan Zhang, Xi Nan, Bei Zhang, Hao Wu, Xianchang Zeng, Zhengbo Song, Shumin Li, Jiaoli Wang, Shaofang Xie, Gensheng Zhang, Huiqing Xiu, Jianli Wang, Jufeng Guo, Pingli Wang, Zhijian Cai, Yunfang Zhen, Yingying Shen
Journal: Theranostics (2024)

Background: CD93 reportedly facilitates tumor angiogenesis.However, whether CD93 regulates antitumor immunity remains undeciphered.Methods: Lung tumor tissues, malignant pleural effusions (MPEs) were obtained from lung cancer patients.Blood was obtained from healthy volunteers and lung cancer patients with anti-PD-1 therapy.Furthermore, p53 fl/fl LSL-Kras G12D , Ccr7 -/-, Cd93 -/-mice and CD11c-DTR mice were generated.Specifically, EM, NTA and western blotting were utilized to identify Tumor extracellular vesicles (TEVs).EV labeling, detection of EV uptake in vitro and in vivo, degradation of EV proteins and RNAs were performed to detect the role of TEVs in tumor progression.Pleural mesothelial cells (pMCs) were isolated to investigate related signaling pathways.Recombinant proteins and antibodies were generated to test which antibody was the most effective one to increase CCL21a in p-pMCs.RNA-Seq, MiRNA array, luciferase reporter assay, endothelial tube formation assay, protein labeling and detection, transfection of siRNAs and the miRNA mimic and inhibitor, chemotaxis assay, immunohistochemical staining, flow cytometry, Real-time PCR, and ELISA experiments were performed.Results: We show that CD93 of pMCs reduced lung tumor migration of dendritic cells by preventing pMCs from secreting CCL21, thereby suppressing systemic anti-lung tumor T-cell responses.TEV-derived miR-5110 promotes CCL21 secretion by downregulating pMC CD93, whereas C1q, increasing in tumor individuals, suppresses CD93-mediated CCL21 secretion.CD93-blocking antibodies (anti-CD93) inhibit lung tumor growth better than VEGF receptor-blocking antibodies because anti-CD93 inhibit tumor angiogenesis and promote CCL21 secretion from pMCs.Anti-CD93 also overcome lung tumor resistance to anti-PD-1 therapy.Furthermore, lung cancer patients with higher serum EV-derived miR-5193 (human miR-5110 homolog) are more sensitive to anti-PD-1 therapy, while patients with higher serum C1q are less sensitive, consistent with their regulatory functions on CD93.Conclusions: Our study identifies a crucial role of CD93 in controlling anti-lung tumor immunity and suggests a promising approach for lung tumor therapy.
Comprehensive characterization of early-programmed tumor microenvironment by tumor-associated macrophages reveals galectin-1 as an immune modulatory target in breast cancer
Authors: Hyewon Chung, Park Gyu-mi, Yi Rang Na, Yun-Sang Lee, Hongyoon Choi, Seung Hyeok Seok
Journal: Theranostics (2024)

In recent years, there has been considerable interest in the therapeutic targeting of tumor-associated macrophages (TAMs) to modulate the tumor microenvironment (TME), resulting in antitumoral phenotypes. However, key mediators suitable for TAM-mediated remodeling of the TME remain poorly understood.
Palmitoylation of PKCδ by ZDHHC5 in hypothalamic microglia presents as a therapeutic target for fatty liver disease
Authors: Yan-Hang Wang, Xin Chen, Yi-Zhen Bai, Peng Gao, Zhuo Yang, Qiang Guo, Ying-Yuan Lu, Jiao Zheng, Dan Liu, Jun Yang, Peng-Fei Tu, Ke-Wu Zeng
Journal: Theranostics (2024)

The hypothalamus plays a fundamental role in controlling lipid metabolism through neuroendocrine signals.However, there are currently no available drug targets in the hypothalamus that can effectively improve human lipid metabolism.In this study, we found that the antimalarial drug artemether (ART) significantly improved lipid metabolism by specifically inhibiting microglial activation in the hypothalamus of high-fat diet-induced mice.Mechanically, ART protects the thyrotropin-releasing hormone (TRH) neurons surrounding microglial cells from inflammatory damage and promotes the release of TRH into the peripheral circulation.As a result, TRH stimulates the synthesis of thyroid hormone (TH), leading to a significant improvement in hepatic lipid disorders.Subsequently, we employed a biotin-labeled ART chemical probe to identify the direct cellular target in microglial cells as protein kinase Cδ (PKCδ).Importantly, ART directly targeted PKCδ to inhibit its palmitoylation modification by blocking the binding of zinc finger DHHC-type palmitoyltransferase 5 (ZDHHC5), which resulted in the inhibition of downstream neuroinflammation signaling.In vivo, hypothalamic microglia-specific PKCδ knockdown markedly impaired ART-dependent neuroendocrine regulation and lipid metabolism improvement in mice.Furthermore, single-cell transcriptomics analysis in human brain tissues revealed that the level of PKCδ in microglia positively correlated with individuals who had hyperlipemia, thereby highlighting a clinical translational value.Collectively, these data suggest that the palmitoylation of microglial PKCδ in the hypothalamus plays a role in modulating peripheral lipid metabolism through hypothalamus-liver communication, and provides a promising therapeutic target for fatty liver diseases.
Initial IL-10 production dominates the therapy of mesenchymal stem cell scaffold in spinal cord injury
Authors: Lijun Yang, Jian Cao, Yiwen Du, Xunqi Zhang, Wenxiang Hong, Bowen Peng, Jiahe Wu, Qinjie Weng, Jiajia Wang, Jianqing Gao
Journal: Theranostics (2024)

Spinal cord injury (SCI) is an acute damage to the central nervous system that results in severe morbidity and permanent disability. Locally implanted scaffold systems with immobilized mesenchymal stem cells (MSCs) have been widely proven to promote locomotor function recovery in SCI rats; however, the underlying mechanism remains elusive.
Quaternization drives spleen-to-lung tropism conversion for mRNA-loaded lipid-like nanoassemblies
Authors: Yixuan Huang, Jiacai Wu, Sanpeng Li, Zhen Liu, Zhenghua Li, Boping Zhou, Bin Li
Journal: Theranostics (2024)

As the overwhelming majority of advanced mRNA delivery systems are preferentially accumulated in the liver, there is an accelerating growth in the demand for the development of non-liver mRNA delivery platforms.
Reciprocal interactions between malignant cells and macrophages enhance cancer stemness and M2 polarization in HBV-associated hepatocellular carcinoma
Authors: Qingyang Zhang, Yu-Man Tsui, Vanilla Xin Zhang, Anna Jingyi Lu, Joyce Man-Fong Lee, Eva Lee, Gary Cheuk-Hang Cheung, Po-Man Li, Elaine Tin-Yan Cheung, Nam-Hung Chia, Irene Lai-Oi Lo, Albert Chi-Yan Chan, Tan-To Cheung, Irene Oi-Lin Ng, Daniel Wai-Hung Ho
Journal: Theranostics (2024)

Background:The tumor microenvironment of cancers has emerged as a crucial component in regulating cancer stemness and plays a pivotal role in cell-cell communication.However, the specific mechanisms underlying these phenomena remain poorly understood.Methods: We performed the single-cell RNA sequencing (scRNA-seq) on nine HBV-associated hepatocellular carcinoma (HCC) patients.The heterogeneity of the malignant cells in pathway functions, transcription factors (TFs) regulation, overall survival, stemness, as well as ligand-receptor-based intercellular communication with macrophages were characterized.The aggressive and stemness feature for the target tumor subclone was validated by the conduction of in vitro assays including sphere formation, proliferation, Annexin V apoptosis, flow cytometry, siRNA library screening assays, and multiple in vivo preclinical mouse models including mouse hepatoma cell and human HCC cell xenograft models with subcutaneous or orthotopic injection.Results: Our analysis yielded a comprehensive atlas of 31,664 cells, revealing a diverse array of malignant cell subpopulations.Notably, we identified a stemness-related subclone of HCC cells with concurrent upregulation of CD24, CD47, and ICAM1 expression that correlated with poorer overall survival.Functional characterization both in vitro and in vivo validated S100A11 as one of the top downstream mediators for tumor initiation and stemness maintenance of this subclone.Further investigation of cell-cell communication within the tumor microenvironment revealed a propensity for bi-directional crosstalk between this stemness-related subclone and tumor-associated macrophages (TAMs).Co-culture study showed that this interaction resulted in the maintenance of the expression of cancer stem cell markers and driving M2-like TAM polarization towards a pro-tumorigenic niche.We also consolidated an inverse relationship between the proportions of TAMs and tumor-infiltrating T cells.Conclusions: Our study highlighted the critical role of stemness-related cancer cell populations in driving an immunosuppressive tumor microenvironment and identified the S100A11 gene as a key mediator for stemness maintenance in HCC.Moreover, our study provides support that the maintenance of cancer stemness is more attributed to M2 polarization than the recruitment of the TAMs.
Endometrial organoids: a reservoir of functional mitochondria for uterine repair
Authors: Sun-Young Hwang, Danbi Lee, Gaeun Lee, Jungho Ahn, Yu-Gyeong Lee, Hwa Seon Koo, Youn-Jung Kang
Journal: Theranostics (2024)

Background: Asherman's syndrome (AS) is a dreadful gynecological disorder of the uterus characterized by intrauterine adhesion with severe fibrotic lesions, resulting in a damaged basalis layer with infertility.Despite extensive research on overcoming AS, evidence-based effective and reproducible treatments to improve the structural and functional morphology of the AS endometrium have not been established.Methods: Endometrial organoids generated from human or mouse endometrial tissues were transplanted into the uterine cavity of a murine model of AS to evaluate their transplantable feasibility to improve the AS uterine environment.The successful engraftment of organoid was confirmed by detection of human mitochondria and cytosol (for human endometrial organoid) or enhanced green fluorescent protein signals (for mouse endometrial organoid) in the recipient endometrium.The therapeutic effects mediated by organoid transplantation were examined by the measurements of fibrotic lesions, endometrial receptivity and angiogenesis, and fertility assessment by recording the number of implantation sites and weighing the fetuses and placenta.To explore the cellular and molecular mechanisms underlying the recovery of AS endometrium, we evaluated the status of mitochondrial movement and biogenetics in organoid transplanted endometrium.Results: Successfully engrafted endometrial organoids with similar morphological and molecular features to the parental tissues dramatically repaired the AS-induced damaged endometrium, significantly reducing fibrotic lesions and increasing fertility outcomes in mice.Moreover, dysfunctional mitochondria in damaged tissues, which we propose might be a key cellular feature of the AS endometrium, was fully recovered by functional mitochondria transferred from engrafted endometrial organoids.Endometrial organoid-originating mitochondria restored excessive collagen accumulation in fibrotic lesions and shifted uterine metabolic environment to levels observed in the normal endometrium.Conclusions: Our findings suggest that endometrial organoid-originating mitochondria might be key players to mediate uterine repair resulting in fertility enhancement by recovering abrogated metabolic circumstance of the endometrium with AS.Further studies addressing the clinical applicability of endometrial organoids may aid in identifying new therapeutic strategies for infertility in patients with AS.
ALDH1A1 drives prostate cancer metastases and radioresistance by interplay with AR- and RAR-dependent transcription
Authors: Ielizaveta Gorodetska, Anne Offermann, Jakob Püschel, Vasyl Lukiyanchuk, Diana Gaete, Anastasia Kurzyukova, Vera Freytag, Marie-Therese Haider, Christina S Fjeldbo, Simona Di Gaetano, Franziska Maria Schwarz, Shivaprasad Patil, Angelika Borkowetz, Holger H. H. Erb, Aria Baniahmad, Jovan Mircetic, Heidi Lyng, Steffen Löck, Annett Linge, Tobias Lange, Franziska Knopf, Ben Wielockx, Mechthild Krause, Sven Perner, Anna Dubrovska
Journal: Theranostics (2024)

Current therapies for metastatic osseous disease frequently fail to provide a durable treatment response. To date, there are only limited therapeutic options for metastatic prostate cancer, the mechanisms that drive the survival of metastasis-initiating cells are poorly characterized, and reliable prognostic markers are missing. A high aldehyde dehydrogenase (ALDH) activity has been long considered a marker of cancer stem cells (CSC). Our study characterized a differential role of ALDH1A1 and ALDH1A3 genes as regulators of prostate cancer progression and metastatic growth.
Lower-grade gliomas surgery guided by GRPR-targeting PET/NIR dual-modality image probe: a prospective and single-arm clinical trial
Authors: Liangpeng Chen, Jingjing Zhang, Chongwei Chi, Wenqiang Che, Gehong Dong, Junmei Wang, Yanru Du, Rongxi Wang, Zhaohui Zhu, Jie Tian, Nan Ji, Xiaoyuan Chen, Deling Li
Journal: Theranostics (2024)

Purpose: Lower-grade gliomas (LGGs) are a group of infiltrative growing glial brain tumors characterized by intricate intratumoral heterogeneity and subtle visual appearance differences from non-tumor tissue, which can lead to errors in pathologic tissue sampling.Although 5-ALA fluorescence has been an essential method for visualizing gliomas during surgery, its effectiveness is limited in the case of LGGs due to low sensitivity.Therefore, we developed a novel PET/NIR dual-modality image probe targeting gastrin-releasing peptide receptor (GRPR) in glioma cells to enhance tumor visualization and improve the accuracy of sampling.Methods: A prospective, non-randomized, single-center feasibility clinical trial (NCT 03407781) was conducted in the referral center from October 21, 2016, to August 17, 2018.Consecutive enrollment included patients suspected of having LGGs and considered suitable candidates for surgical removal.Group 1 comprised ten patients who underwent preoperative 68 Ga-IRDye800CW-BBN PET/MRI assessment followed by intraoperative fluorescence-guided surgery.Group 2 included 42 patients who underwent IRDye800CW-BBN fluorescence-guided surgery.The primary endpoints were the predictive value of preoperative PET imaging for intraoperative fluorescence and the sensitivity and specificity of fluorescence-guided sampling.Results: Thirty-nine patients were included in the in-depth analysis of endpoints, with 25 (64.1%)exhibiting visible fluorescence, while 14 (35.9%) did not.The preoperative positive PET uptake exhibited a greater accuracy in predicting intraoperative fluorescence compared to MRI enhancement (100% [10/10] vs. 87.2%
Psychotropic Drug–Related Weight Gain and Its Treatment
Authors: Roger S. McIntyre, Angela T.H. Kwan, Joshua D. Rosenblat, Kayla M. Teopiz, Rodrigo B. Mansur
Journal: American Journal of Psychiatry (2024)

Psychotropic drug–related weight gain (PDWG) is a common occurrence and is highly associated with non-initiation, discontinuation, and dissatisfaction with psychiatric drugs. Moreover, PDWG intersects with the elevated risk for obesity and associated morbidity that has been amply reported in the psychiatric population. Evidence indicates that differential liability for PDWG exists for antipsychotics, antidepressants, and anticonvulsants. During the past two decades, agents within these classes have become available with significantly lower or no liability for PDWG and as such should be prioritized. Although lithium is associated with weight gain, the overall extent of weight gain is significantly lower than previously estimated. The benefit of lifestyle and behavioral modification for obesity and/or PDWG in psychiatric populations is established, with effectiveness similar to that in the general population. Metformin is the most studied pharmacological treatment in the prevention and treatment of PDWG, and promising data are emerging for glucagon-like peptide-1 (GLP-1) receptor agonists (e.g., liraglutide, exenatide, semaglutide). Most pharmacologic antidotes for PDWG are supported with low-confidence data (e.g., topiramate, histamine-2 receptor antagonists). Future vistas for pharmacologic treatment for PDWG include large, adequately controlled studies with GLP-1 receptor agonists and possibly GLP-1/glucose-dependent insulinotropic polypeptide co-agonists (e.g., tirzepatide) as well as specific dietary modifications.
Activation‐Induced Senescent Cell Death based on Chiral CoHAu Nanoassemblies with Enantioselective Cascade‐Catalytic Ability
Authors: Si Li, Fang Wang, Xinhe Xing, Xiaoyong Yue, Shan Sun, Hengwei Lin, Chuanlai Xu
Journal: Advanced Healthcare Materials (2023)

Abstract Chirality is common in nature, which determines the high enantioselectivity of living systems. Selecting suitable chiral configurations is of great meaning for nanostructures to function better in biological systems. In this study, chiral Co 3 O 4 ‐H 2 TPPS‐Au (CoHAu) nanoassemblies are constructed to accelerate the production ∙OH by consuming D ‐glucose ( D ‐Glu, widely spread in nature) based on their outstanding enantioselective cascade‐catalytic abilities. In particular, D ‐CoHAu nanoassemblies are more effective in the catalytic conversion of D ‐Glu than L ‐CoHAu nanoassemblies. This phenomenon is due to the stronger binding affinity of D ‐CoHAu nanoassemblies indicated by the lower K m value. Moreover, D ‐CoHAu nanoassemblies display excellent consumption‐ability of D ‐Glu and production of ∙OH in living cells, which can eliminate senescent cells effectively based on their intracellular enantioselective cascade‐catalysis. This research establishes the foundation for bio‐mimicking nanostructures with unique functionalities to regulate abnormal biological activities better.
[<sup>89</sup>Zr]-CD8 ImmunoPET imaging of glioblastoma multiforme response to combination oncolytic viral and checkpoint inhibitor immunotherapy reveals CD8 infiltration differential changes in preclinical models
Authors: Carlos A. Gallegos, Yun Lu, Jennifer C. Clements, Patrick N. Song, Shannon E. Lynch, Alessandro Mascioni, Fang Jia, Yolanda E. Hartman, Adriana V. F. Massicano, Hailey A. Houson, Suzanne E. Lapi, Jason M. Warram, James M. Markert, Anna G. Sorace
Journal: Theranostics (2024)

Rationale: Novel immune-activating therapeutics for the treatment of glioblastoma multiforme (GBM) have shown potential for tumor regression and increased survival over standard therapies.However, immunotherapy efficacy remains inconsistent with response assessment being complicated by early treatment-induced apparent radiological tumor progression and slow downstream effects.This inability to determine early immunotherapeutic benefit results in a drastically decreased window for alternative, and potentially more effective, treatment options.The objective of this study is to evaluate the effects of combination immunotherapy on early CD8 + cell infiltration and its association with long term response in orthotopic syngeneic glioblastoma models.Methods: Luciferase positive GBM orthotopic mouse models (GSC005-luc) were imaged via [ 89 Zr]-CD8 positron emission tomography (PET) one week following treatment with saline, anti-PD1, M002 oncolytic herpes simplex virus (oHSV) or combination immunotherapy.Subsequently, brains were excised, imaged via [ 89 Zr]-CD8 ImmunoPET and evaluated though autoradiography and histology for H&E and CD8 immunohistochemistry. Longitudinal immunotherapeutic effects were evaluated through [ 89 Zr]-CD8 PET imaging one-and three-weeks following treatment, with changes in tumor volume monitored on a three-day basis via bioluminescence imaging (BLI).Response classification was then performed based on long-term BLI signal changes.Statistical analysis was performed between groups using one-way ANOVA and two-sided unpaired T-test, with p < 0.05 considered significant.Correlations between imaging and biological validation were assessed via Pearson's correlation test.Results: [ 89 Zr]-CD8 PET standardized uptake value (SUV) quantification was correlated with ex vivo SUV quantification (r = 0.61, p < 0.01), autoradiography (r = 0.46, p < 0.01), and IHC tumor CD8 + cell density (r = 0.55, p < 0.01).Classification of therapeutic responders, via bioluminescence signal, revealed a more homogeneous CD8 + immune cell distribution in responders (p < 0.05) one-week following immunotherapy.Conclusions: Assessment of early CD8 + cell infiltration and distribution in the tumor microenvironment provides potential imaging metrics for the characterization of oHSV and checkpoint blockade immunotherapy response in GBM.The combination therapies showed enhanced efficacy compared to single agent immunotherapies.Further development of immune-focused imaging methods can provide clinically relevant Ivyspring International
Antibacterial micro/nanomotors: current research progress, challenges, and opportunities
Authors: Xin-Yang Liu, Rui-Fang Li, Jun Jia, Zi-Li Yu
Journal: Theranostics (2024)

Bacterial infections remain a formidable threat to human health, a situation exacerbated by the escalating problem of antibiotic resistance. While alternative antibacterial strategies such as oxidants, heat treatments, and metal nanoparticles (NPs) have shown potential, they come with significant drawbacks, ranging from non-specificity to potential environmental concerns. In the face of these challenges, the rapid evolution of micro/nanomotors (MNMs) stands out as a revolutionary development in the antimicrobial arena. MNMs harness various forms of energy and convert it into a substantial driving force, offering bright prospects for combating microbial threats. MNMs' mobility allows for swift and targeted interaction with bacteria, which not only improves the carrying potential of therapeutic agents but also narrows the required activation range for non-drug antimicrobial interventions like photothermal and photodynamic therapies, substantially improving their bacterial clearance rates. In this review, we summarized the diverse propulsion mechanisms of MNMs employed in antimicrobial applications and articulated their multiple functions, which include direct bactericidal action, capture and removal of microorganisms, detoxification processes, and the innovative detection of bacteria and associated toxins. Despite MNMs' potential to revolutionize antibacterial research, the translation from laboratory to clinical use remains challenging. Based on the current research status, we summarized the potential challenges and possible solutions and also prospected several key directions for future studies of MNMs for antimicrobial purposes. Collectively, by highlighting the important knowns and unknowns of antimicrobial MNMs, our present review would help to light the way forward for the field of antimicrobial MNMs and prevent unnecessary blindness and detours.