tbuckley/cabot-search huggingface dataset:
High-content stimulated Raman histology of human breast cancer
Authors: Hongli Ni, Chinmayee Prabhu Dessai, Haonan Lin, Wei Wang, Shaoxiong Chen, Yuhao Yuan, Xiaowei Ge, Jianpeng Ao, Nolan Vild, Ji-Xin Cheng
Journal: Theranostics (2024)

Histological examination is crucial for cancer diagnosis, however, the labor-intensive sample preparation involved in the histology impedes the speed of diagnosis.Recently developed two-color stimulated Raman histology could bypass the complex tissue processing to generates result close to hematoxylin and eosin staining, which is one of the golden standards in cancer histology.Yet, the underlying chemical features are not revealed in two-color stimulated Raman histology, compromising the effectiveness of prognostic stratification.Here, we present a high-content stimulated Raman histology (HC-SRH) platform that provides both morphological and chemical information for cancer diagnosis based on un-stained breast tissues.Methods: By utilizing both hyperspectral SRS imaging in the C-H vibration window and sparsity-penalized unmixing of overlapped spectral profiles, HC-SRH enabled high-content chemical mapping of saturated lipids, unsaturated lipids, cellular protein, extracellular matrix (ECM), and water.Spectral selective sampling was further implemented to boost the speed of HC-SRH.To show the potential for clinical use, HC-SRH using a compact fiber laser-based stimulated Raman microscope was demonstrated.Harnessing the wide and rapid tuning capability of the fiber laser, both C-H and fingerprint vibration windows were accessed.Results: HC-SRH successfully mapped unsaturated lipids, cellular protein, extracellular matrix, saturated lipid, and water in breast tissue.With these five chemical maps, HC-SRH provided distinct contrast for tissue components including duct, stroma, fat cell, necrosis, and vessel.With selective spectral sampling, the speed of HC-SRH was improved by one order of magnitude.The fiber-laser-based HC-SRH produced the same image quality in the C-H window as the state-of-the-art solid laser.In the fingerprint window, nucleic acid and solid-state ester contrast was demonstrated.Conclusions: HC-SRH provides both morphological and chemical information of tissue in a label-free manner.The chemical information detected is beyond the reach of traditional hematoxylin and eosin staining and heralds the potential of HC-SRH for biomarker discovery.
Development of CD46 targeted alpha theranostics in prostate cancer using <sup>134</sup>Ce/<sup>225</sup>Ac-Macropa-PEG<sub>4</sub>-YS5
Authors: Kondapa Naidu Bobba, Anil P. Bidkar, Anju Wadhwa, Niranjan Meher, Suchi Drona, Alexandre M. Sorlin, Scott Bidlingmaier, Li Zhang, David M. Wilson, Emily Chan, Nancy Y. Greenland, Rahul Aggarwal, Henry F. VanBrocklin, Jiang He, Jonathan Chou, Youngho Seo, Bin Liu, Robert R. Flavell
Journal: Theranostics (2024)

Ac, a long-lived α-emitter with a half-life of 9.92 days, has garnered significant attention as a therapeutic radionuclide when coupled with monoclonal antibodies and other targeting vectors. Nevertheless, its clinical utility has been hampered by potential off-target toxicity, a lack of optimized chelators for
The mitochondria‒paraspeckle axis regulates the survival of transplanted stem cells under oxidative stress conditions
Authors: Meng Zhao, Shuyun Liu, Yizhuo Wang, Ke Lv, Peng Lou, Pingya Zhou, Jiaying Zhu, Lan Li, Jingqiu Cheng, Yanrong Lu, Jingping Liu
Journal: Theranostics (2024)

Rationale: Stem cell-based therapies have emerged as promising tools for tissue engineering and regenerative medicine, but their therapeutic efficacy is largely limited by the oxidative stress-induced loss of transplanted cells at injured tissue sites.To address this issue, we aimed to explore the underlying mechanism and protective strategy of ROS-induced MSC loss.Methods: Changes in TFAM (mitochondrial transcription factor A) signaling, mitochondrial function, DNA damage, apoptosis and senescence in MSCs under oxidative stress conditions were assessed using real-time PCR, western blotting and RNA sequencing, etc.The impact of TFAM or lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) knockdown or overexpression on mitochondrial function, DNA damage repair, apoptosis and senescence in MSCs was also analyzed.The effect of mitochondrion-targeted antioxidant (Mito-TEMPO) on the survival of transplanted MSCs was evaluated in a mouse model of renal ischemia/reperfusion (I/R) injury.Results: Mitochondrial ROS (mtROS) bursts caused defects in TFAM signaling and overall mitochondrial function, which further impaired NEAT1 expression and its mediated paraspeckle formation and DNA repair pathways in MSCs, thereby jointly promoting MSC senescence and death under oxidative stress.In contrast, targeted inhibition of the mtROS bursts is a sufficient strategy for attenuating early transplanted MSC loss at injured tissue sites, and coadministration of Mito-TEMPO improved the local retention of transplanted MSCs and reduced oxidative injury in ischemic kidneys.Conclusions: This study identified the critical role of the mitochondria-paraspeckle axis in regulating cell survival and may provide insights into developing advanced stem cell therapies for tissue engineering and regenerative medicine.
Polycomb repressive complex 1 modulates granulosa cell proliferation in early folliculogenesis to support female reproduction
Authors: Meng Gao, Tuo Zhang, Tengxiang Chen, Ziqi Chen, Zijian Zhu, Yang Wen, Shaogang Qin, Yibing Bao, Ting Zhao, Hengxing Li, Longping Liu, Ming Hao, Jianbin Wang, Fengchao Wang, Haibin Wang, Bo Zhou, Hua Zhang, Guoliang Xia, Chao Wang
Journal: Theranostics (2024)

Premature ovarian insufficiency (POI) is an accelerated reduction in ovarian function inducing infertility. Folliculogenesis defects have been reported to trigger POI as a consequence of ovulation failure. However, the underlying mechanisms remain unclear due to the genetic complexity and heterogeneity of POI.
Re-analysis of single-cell transcriptomics reveals a critical role of macrophage-like smooth muscle cells in advanced atherosclerotic plaque
Authors: Xue Gong, Yunchang Liu, Huiying Liu, Nian Cao, Liping Zeng, Miao Tian, Chunyu Zeng, Yijie Hu, Runjun Zhang, Yundai Chen, Gengze Wu
Journal: Theranostics (2024)

Aims: Smooth muscle cell (SMC) remodeling poses a critical feature in the development and progression of atherosclerosis.Although fate mapping and in silicon approaches have expanded SMC phenotypes in atherosclerosis, it still remains elusive about the contributions of individual SMC phenotypes and molecular dynamics to advanced atherosclerotic plaque.Methods: Using single-cell transcriptome, we investigated cellular compositions of human carotid plaque laden with atherosclerotic core, followed by in vivo experiments utilizing SMC-lineage tracing technology, bulk RNA sequencing (RNA-seq) and both in vivo and in vitro validation of the underlying molecular mechanism.Results: 5 functionally distinct SMC subtypes were uncovered based on transcriptional features (described as contractile, fibroblast-like, osteogenic, synthetic and macrophage-like) within the niche.A proinflammatory, macrophage-like SMC subtype displaying an intermediary phenotype between SMC and macrophage, exhibits prominent potential in destabilizing plaque.At the molecular level, we explored cluster-specific master regulons by algorithm, and identified interferon regulatory factor-8 (IRF8) as a potential stimulator of SMC-to-macrophage transdifferentiation via activating nuclear factor-κB (NF-κB) signaling.Conclusions: Our study illustrates a comprehensive cell atlas and molecular landscape of advanced atherosclerotic lesion, which might renovate current understanding of SMC biology in atherosclerosis.
Metal nanoparticle hybrid hydrogels: the state-of-the-art of combining hard and soft materials to promote wound healing
Authors: Yuxiang Wang, Mengya Zhang, Zhenzhen Yan, Shizhao Ji, Shichu Xiao, Jie Gao
Journal: Theranostics (2024)

Wounds represent a grave affliction that profoundly impacts human well-being.Establishing barriers, preventing infections, and providing a conducive microenvironment constitute the crux of wound therapy.Hydrogel, a polymer with an intricate three-dimensional lattice, serves as a potent tool in erecting physical barriers and nurturing an environment conducive to wound healing.This enables effective control over exudation, hemostasis, accelerated wound closure, and diminished scar formation.As a result, hydrogels have gained extensive traction in the realm of wound treatment.Metallic nanoparticle carriers, characterized by their multifaceted responses encompassing acoustics, optics, and electronics, have demonstrated efficacy in wound management.Nevertheless, these carriers encounter challenges associated with swift clearance and nonuniform effectiveness.The hybridization of metallic nanoparticle carriers with hydrogels overcomes the shortcomings inherent in metallic nanoparticle-based wound therapy.This amalgamation not only addresses the limitations but also augments the mechanical robustness of hydrogels.It confers upon them attributes such as environmental responsiveness and multifunctionality, thereby synergizing strengths and compensating for weaknesses.This integration culminates in the precise and intelligent management of wounds.This review encapsulates the structural classifications, design strategies, therapeutic applications, and underlying mechanisms of metal nanoparticle hybrid hydrogels in the context of acute and chronic wound treatment.The discourse delves into the generation of novel or enhanced attributes arising from hybridization and how the current paradigm of wound therapy leverages these attributes.Amidst this continually evolving frontier, the potential of metal nanoparticle hybrid hydrogels to revolutionize wound treatment is underscored.
Emerging role of extracellular vesicles in diabetic retinopathy
Authors: Junyan Zhu, Jin Huang, Yaoxiang Sun, Wenrong Xu, Hui Qian
Journal: Theranostics (2024)

Diabetic retinopathy (DR), a complex complication of diabetes mellitus (DM), is a leading cause of adult blindness.Hyperglycemia triggers DR, resulting in microvascular damage, glial apoptosis, and neuronal degeneration.Inflammation and oxidative stress play crucial roles during this process.Current clinical treatments for DR primarily target the advanced retinal disorder but offer limited benefits with inevitable side effects.Extracellular vesicles (EVs) exhibit unique morphological features, contents, and biological properties and can be found in cell culture supernatants, various body fluids, and tissues.In DR, EVs with specific cargo composition would induce the reaction of receptor cell once internalized, mediating cellular communication and disease progression.Increasing evidence indicates that monitoring changes in EV quantity and content in DR can aid in disease diagnosis and prognosis.Furthermore, extensive research is investigating the potential of these nanoparticles as effective therapeutic agents in preclinical models of DR.This review explores the current understanding of the pathological effects of EVs in DR development, discusses their potential as biomarkers and therapeutic strategies, and paves the way for further research and therapeutic advancements.
Single-cell RNA sequencing reveals S100a9<sup>hi</sup> macrophages promote the transition from acute inflammation to fibrotic remodeling after myocardial ischemia‒reperfusion
Authors: Shichun Shen, Meng Zhang, Xiaohe Wang, Qiaoling Liu, Huimin Su, Bingyi Sun, Zhiqing Guo, Beiduo Tian, Hong Gan, Chen Gong, Likun Ma
Journal: Theranostics (2024)

Rationale:The transition from acute inflammation to fibrosis following myocardial ischemia-reperfusion (MIR) significantly affects prognosis.Macrophages play a pivotal role in inflammatory damage and repair after MIR.However, the heterogeneity and transformation mechanisms of macrophages during this transition are not well understood.Methods: In this study, we used single-cell RNA sequencing (scRNA-seq) and mass cytometry to examine murine monocyte-derived macrophages after MIR to investigate macrophage subtypes and their roles in the MIR process.S100a9 -/-mice were used to establish MIR model to clarify the mechanism of alleviating inflammation and fibrosis after MIR.Reinfusion of bone marrow-derived macrophages (BMDMs) after macrophage depletion (MD) in mice subjected to MIR were performed to further examine the role of S100a9 hi macrophages in MIR.Results: We identified a unique subtype of S100a9 hi macrophages that originate from monocytes and are involved in acute inflammation and fibrosis.These S100a9 hi macrophages infiltrate the heart as early as 2 h post-reperfusion and activate the Myd88/NFκB/NLRP3 signaling pathway, amplifying inflammatory responses.As the tissue environment shifts from proinflammatory to reparative, S100a9 activates transforming growth factor-β (Tgf-β)/p-smad3 signaling.This activation not only induces the transformation of myocardial fibroblasts to myofibroblasts but also promotes fibrosis via the macrophage-to-myofibroblast transition (MMT).Targeting S100a9 with a specific inhibitor could effectively mitigate acute inflammatory damage and halt the progression of fibrosis, including MMT.Conclusion: S100a9 hi macrophages are a promising therapeutic target for managing the transition from inflammation to fibrosis after MIR.
Midline-1 regulates effector T cell motility in experimental autoimmune encephalomyelitis via mTOR/microtubule pathway
Authors: Yingying Wei, Wenjuan Li, Jie Huang, Zachary Braunstein, Xinxin Liu, Xinlu Li, Jeffrey Deiuliis, Jun Chen, Xinwen Min, Handong Yang, Quan Gong, Leya He, Zheng Liu, Lingli Dong, Jixin Zhong
Journal: Theranostics (2024)

Background: Effector T cell activation, migration, and proinflammatory cytokine production are crucial steps in autoimmune disorders such as multiple sclerosis (MS).While several therapeutic approaches targeting T cell activation and proinflammatory cytokines have been developed for the treatment of autoimmune diseases, there are no therapeutic agents targeting the migration of effector T cells, largely due to our limited understanding of regulatory mechanisms of T cell migration in autoimmune disease.Here we reported that midline-1 (Mid1) is a key regulator of effector T cell migration in experimental autoimmune encephalomyelitis (EAE), a widely used animal model of MS.Methods: Mid1 -/-mice were generated by Crispr-Cas9 technology.T cell-specific Mid1 knockout chimeric mice were generated by adoptive transfer of Mid1 -/-T cells into lymphocyte deficient Rag2 -/-mice.Mice were either immunized with MOG35-55 (active EAE) or received adoptive transfer of pathogenic T cells (passive EAE) to induce EAE.In vitro Transwell ® assay or in vivo footpad injection were used to assess the migration of T cells.Results: Mid1 was significantly increased in the spinal cord of wild-type (Wt) EAE mice and disruption of Mid1 in T cells markedly suppressed the development of both active and passive EAE.Transcriptomic and flow cytometric analyses revealed a marked reduction in effector T cell number in the central nervous system of Mid1 -/-mice after EAE induction.Conversely, an increase in the number of T cells was observed in the draining lymph nodes of Mid1 -/-mice.Mice that were adoptively transferred with pathogenic Mid1 -/-T cells also exhibited milder symptoms of EAE, along with a lower T cell count in the spinal cord.Additionally, disruption of Mid1 significantly inhibited T-cell migration both in vivo and in vitro.RNA sequencing suggests a suppression in multiple inflammatory pathways in Mid1 -/-mice, including mTOR signaling that plays a critical role in cell migration.Subsequent experiments confirmed the interaction between Mid1 and mTOR.Suppression of mTOR with rapamycin or microtubule spindle formation with colcemid blunted the regulatory effect of Mid1 on T cell migration.In addition, mTOR agonists MHY1485 and 3BDO restored the migratory deficit caused by Mid1 depletion. Conclusion:Our data suggests that Mid1 regulates effector T cell migration to the central nervous system via mTOR/microtubule pathway in EAE, and thus may serve as a potential therapeutic target for the treatment of MS.
The DNA-dependent protein kinase catalytic subunit exacerbates endotoxemia-induced myocardial microvascular injury by disrupting the MOTS-c/JNK pathway and inducing profilin-mediated lamellipodia degradation
Authors: Rongjun Zou, Wanting Shi, Xing Chang, Miao Zhang, Songtao Tan, Ruibing Li, Hao Zhou, Yukun Li, Ge Wang, Weihui Lv, Xiaoping Fan
Journal: Theranostics (2024)

Rationale:The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) promotes pathological mitochondrial fission during septic acute kidney injury.The mitochondrial open reading frame of the 12S rRNA type-c (MOTS-c) is a mitochondria-derived peptide that exhibits anti-inflammatory properties during cardiovascular illnesses.We explored whether endotoxemia-induced myocardial microvascular injury involved DNA-PKcs and MOTS-c dysregulation.Methods: To induce endotoxemia in vivo, endothelial cell-specific DNA-PKcs-knockout mice were injected intraperitoneally with a single dose of lipopolysaccharide (10 mg/kg) and evaluated after 72 h.Results: Lipopolysaccharide exposure increased DNA-PKcs activity in cardiac microvascular endothelial cells, while pharmacological inhibition or endothelial cell-specific genetic ablation of DNA-PKcs reduced lipopolysaccharide-induced myocardial microvascular dysfunction.Proteomic analyses showed that endothelial DNA-PKcs ablation primarily altered mitochondrial protein expression.Verification assays confirmed that DNA-PKcs drastically repressed MOTS-c transcription by inducing mtDNA breaks via pathological mitochondrial fission.Inhibiting MOTS-c neutralized the endothelial protective effects of DNA-PKcs ablation, whereas MOTS-c supplementation enhanced endothelial barrier function and myocardial microvascular homeostasis under lipopolysaccharide stress.In molecular studies, MOTS-c downregulation disinhibited c-Jun N-terminal kinase (JNK), allowing JNK to phosphorylate profilin-S173.Inhibiting JNK or transfecting cells with a profilin phosphorylation-defective mutant improved endothelial barrier function by preventing F-actin depolymerization and lamellipodial degradation following lipopolysaccharide treatment.Conclusions: DNA-PKcs inactivation during endotoxemia could be a worthwhile therapeutic strategy to restore MOTS-c expression, prevent JNK-induced profilin phosphorylation, improve F-actin polymerization, and enhance lamellipodial integrity, ultimately ameliorating endothelial barrier function and reducing myocardial microvascular injury.
Therapeutic effects of a novel electrode for transcranial direct current stimulation in ischemic stroke mice
Authors: Da Hee Jung, Jae Ho Lee, Hong Ju Lee, Jang Woo Park, Young-Jin Jung, Hwa Kyoung Shin, Byung Tae Choi
Journal: Theranostics (2024)

Rationale: Non-invasive transcranial direct current stimulation (tDCS), a promising stimulation tool to modulate a wide range of brain disorders, has major limitations, such as poor cortical stimulation intensity and focality.We designed a novel electrode for tDCS by conjugating a needle to a conventional ring-based high-definition (HD) electrode to enhance cortical stimulation efficacy.Method: HD-tDCS (43 µA/mm 2 , charge density 51.6 kC/m 2 , 20 min) was administered to male C57BL/6J mice subjected to early-stage ischemic stroke.Behavioral tests were employed to determine the therapeutic effects, and the underlying mechanisms of HD-tDCS were determined by performing RNA sequencing and other biomedical analyses. Results:The new HD-tDCS application, showing a higher electric potential and spatial focality based on computational modeling, demonstrated better therapeutic effects than conventional HD-tDCS in alleviating motor and cognitive deficits, with a decrease in infarct volume and inflammatory response.We assessed different electrode configurations in the new HD electrode; the configurations variously showed potent therapeutic effects, ameliorating neuronal death in the peri-infarct region via N-methyl-D-aspartate-dependent sterol regulatory element-binding protein 1 signaling and related inflammatory factors, further alleviating motor and cognitive deficits in stroke. Conclusion:This new HD-tDCS application showed better therapeutic effects than those with conventional HD-tDCS in early-stage stroke via the amelioration of neuronal death in the penumbra.It may be applied in the early stages of stroke to alleviate neurological impairment.
A novel approach to guide GD2-targeted therapy in pediatric tumors by PET and [<sup>64</sup>Cu]Cu-NOTA-ch14.18/CHO
Authors: Nils Florian Trautwein, Johannes Schwenck, Christian Seitz, Ferdinand Seith, Eduardo Calderón, Sebastian von Beschwitz, Stephan Singer, Gerald Reischl, Rupert Handgretinger, Jürgen Schäfer, Peter Lang, Bernd J. Pichler, Johannes H. Schulte, Christian la Fougère, Helmut Dittmann
Journal: Theranostics (2024)

Background:The tumor-associated disialoganglioside GD2 is a bona fide immunotherapy target in neuroblastoma and other childhood tumors, including Ewing sarcoma and osteosarcoma.GD2-targeting antibodies proved to be effective in neuroblastoma and GD2-targeting chimeric antigen receptors (CAR)expressing T cells as well as natural killer T cells (NKTs) are emerging.However, assessment of intra-and intertumoral heterogeneity has been complicated by ineffective immunohistochemistry as well as sampling bias in disseminated disease.Therefore, a non-invasive approach for the assessment and visualization of GD2 expression in-vivo is of upmost interest and might enable a more appropriate treatment stratification.Methods: Recently, [ 64 Cu]Cu-NOTA-ch14.18/CHO( 64 Cu-GD2), a radiolabeled GD2-antibody for imaging with Positron-Emission-Tomography (PET) was developed.We here report our first clinical patients' series (n = 11) in different pediatric tumors assessed with 64 Cu-GD2 PET/MRI.GD2-expression in tumors and tissue uptake in organs was evaluated by semiquantitative measurements of standardized uptake values (SUV) with PET/MRI on day 1 p.i. (n = 11) as well as on day 2 p.i. (n = 6).Results: In 8 of 9 patients with suspicious tumor lesions on PET/MRI at least one metastasis showed an increased 64 Cu-GD2 uptake and a high tracer uptake (SUVmax > 10) was measured in 4 of those 8 patients.Of note, sufficient image quality with high tumor to background contrast was readily achieved on day 1.In case of 64 Cu-GD2-positive lesions, an excellent tumor to background ratio (at least 6:1) was observed in bones, muscles or lungs, while lower tumor to background contrast was seen in the spleen, liver and kidneys.Furthermore, we demonstrated extensive tumor heterogeneity between patients as well as among different metastatic sites in individual patients.Dosimetry assessment revealed a whole-body dose of only 0.03 mGy/MBq (range 0.02-0.04).Conclusion: 64 Cu-GD2 PET/MRI enables the non-invasive assessment of individual heterogeneity of GD2 expression, which challenges our current clinical practice of patient selection, stratification and immunotherapy application scheme for treatment with anti-GD2 directed therapies.
Transfer RNA derived fragment, tRF-Glu-CTC, aggravates the development of neovascular age-related macular degeneration
Authors: Yu Liang, Lingjie Kong, Yuelu Zhang, Yihan Zhang, Mingsu Shi, Jiaqiu Huang, Hongyu Kong, Siyi Qi, Yunlong Yang, Jiaxu Hong, Meidong Zhu, Xiangjia Zhu, Xinghuai Sun, Shujie Zhang, Lianqun Wu, Chen Zhao
Journal: Theranostics (2024)

Angiogenesis expedites tissue impairment in many diseases, including age-related macular degeneration (AMD), a leading cause of irreversible blindness in elderly. A substantial proportion of neovascular AMD patients, characterized by aberrant choroidal neovascularization (CNV), exhibit poor responses or adverse reactions to anti-VEGF therapy. Herein, we aimed to unveil the function of newly identified transfer RNA-derived small RNA, tRF-Glu-CTC, in the pathology of CNV and determine its potential in inhibiting angiogenesis.