tbuckley/cabot-search huggingface dataset:
The orchestration of cell-cycle reentry and ribosome biogenesis network is critical for cardiac repair
Authors: Yanli Wang, Junchu Tu, Weiliang Wu, Yan Xu, Yujie Li, Xiangbin Pan, Bin Liu, Tonggan Lu, Qingfang Han, Huiling Zhang, Lijuan Jiao, Yu Zhang, Xi-Yong Yu, Zhenya Shen, Yangxin Li
Journal: Theranostics (2024)

Rationale: Myocardial infarction (MI) is a severe global clinical condition with widespread prevalence.The adult mammalian heart's limited capacity to generate new cardiomyocytes (CMs) in response to injury remains a primary obstacle in developing effective therapies.Current approaches focus on inducing the proliferation of existing CMs through cell-cycle reentry.However, this method primarily elevates cyclin dependent kinase 6 (CDK6) and DNA content, lacking proper cytokinesis and resulting in the formation of dysfunctional binucleated CMs.Cytokinesis is dependent on ribosome biogenesis (Ribo-bio), a crucial process modulated by nucleolin (Ncl).Our objective was to identify a novel approach that promotes both DNA synthesis and cytokinesis.Methods: Various techniques, including RNA/protein-sequencing analysis, Ribo-Halo, Ribo-disome, flow cytometry, and cardiac-specific tumor-suppressor retinoblastoma-1 (Rb1) knockout mice, were employed to assess the series signaling of proliferation/cell-cycle reentry and Ribo-bio/cytokinesis. Echocardiography, confocal imaging, and histology were utilized to evaluate cardiac function.Results: Analysis revealed significantly elevated levels of Rb1, bur decreased levels of circASXL1 in the hearts of MI mice compared to control mice.Deletion of Rb1 induces solely cell-cycle reentry, while augmenting the Ribo-bio modulator Ncl leads to cytokinesis.Mechanically, bioinformatics and the loss/gain studies uncovered that circASXL1/CDK6/Rb1 regulates cell-cycle reentry.Moreover, Ribo-Halo, Ribo-disome and circRNA pull-down assays demonstrated that circASXL1 promotes cytokinesis through Ncl/Ribo-bio.Importantly, exosomes derived from umbilical cord mesenchymal stem cells (UMSC-Exo) had the ability to enhance cardiac function by facilitating the coordinated signaling of cell-cycle reentry and Ribo-bio/cytokinesis.These effects were attenuated by silencing circASXL1 in UMSC-Exo. Conclusion:The series signaling of circASXL1/CDK6/Rb1/cell-cycle reentry and circASXL1/Ncl/Ribo-bio/cytokinesis plays a crucial role in cardiac repair.UMSC-Exo effectively repairs infarcted myocardium by stimulating CM cell-cycle reentry and cytokinesis in a circASXL1-dependent manner.This study provides innovative therapeutic strategies targeting the circASXL1 signaling network for MI and offering potential avenues for enhanced cardiac repair.
PRMT6-mediated ADMA promotes p62 phase separation to form a negative feedback loop in ferroptosis
Authors: Lifeng Feng, Lini Chen, Weikai Wang, Qi Wei, Minqiang Chen, Xin Jiang, Shiman Hu, Yuchen Wu, Lian Duan, Liyuan Zhu, Xian Wang, Hongchuan Jin
Journal: Theranostics (2024)

Due to intrinsic defensive response, ferroptosis-activating targeted therapy fails to achieve satisfactory clinical benefits. Though p62-Keap1-Nrf2 axis is activated to form a negative feedback loop during ferroptosis induction, how p62 is activated remains largely unknown.
Microglial circ-UBE2K exacerbates depression by regulating parental gene UBE2K via targeting HNRNPU
Authors: Yujie Cai, Yao Ji, Yingxuan Liu, Dandan Zhang, Zheng Gong, Li Li, Xiongjin Chen, Chunmei Liang, Sifan Feng, Jiongtong Lu, Qinjie Qiu, Zhixiong Lin, Yan Wang, Lili Cui
Journal: Theranostics (2024)

Knowledge about the pathogenesis of depression and treatments for this disease are lacking. Epigenetics-related circRNAs are likely involved in the mechanism of depression and have great potential as treatment targets, but their mechanism of action is still unclear.
FUS-mediated BBB opening leads to transient perfusion decrease and inflammation without acute or chronic brain lesion
Authors: Sébastien Rigollet, Claire Rome, Thomas Ador, Erik Dumont, Chantal Pichon, Anthony Delalande, Emmanuel L. Barbier, Vasile Stupar
Journal: Theranostics (2024)

Impact: The permeabilization of the BBB to deliver therapeutics with MR-guided FUS redefines therapeutic strategies as it improves patient outcomes. To ensure the best translation towards clinical treatment, the evaluation of hemodynamic modifications in the CNS is necessary to refine treatment parameters. Methods: MR-guided FUS was applied at 1.5 MHz with a 50 ms burst every 1 s to open the BBB. CBF, BVf and ADC parameters were monitored with MRI. Cavitation was monitored with a PCD during the FUS sequence and classified with the IUD index into three cavitation levels. We distinctly applied the FUS in the cortex or the striatum. After the BBB permeabilization, neuroinflammation markers were quantified longitudinally. Results: The BBB was successfully opened in all animals in this study and only one animal was classified as "hard" and excluded from the rest of the study. 30 min after FUS-induced BBB opening in the cortex, we measured a 54% drop in CBF and a 13% drop in BVf compared to the contralateral side. After permeabilization of the striatum, a 38% drop in CBF and a 15% drop in BVf were measured. CBF values rapidly returned to baseline, and 90 min after BBB opening, no significant differences were observed. We quantified the subsequent neuroinflammation, noting a significant increase in astrocytic recruitment at 2 days and microglial activation at 1 day after FUS. After 7 days, no more inflammation was visible in the brain. Conclusion: FUS-induced BBB opening transiently modifies hemodynamic parameters such as CBF and BVf, suggesting limited nutrients and oxygen supply to the CNS in the hour following the procedure.
The CEBPB<sup>+</sup> glioblastoma subcluster specifically drives the formation of M2 tumor-associated macrophages to promote malignancy growth
Authors: Yongchang Yang, Xingyu Jin, Yang Xie, Chunlan Ning, Yiding Ai, Haotian Wei, Xing Xu, Xianglian Ge, Tailong Yi, Qiang Huang, Xuejun Yang, Tao Jiang, Xiaoguang Wang, Yingzhe Piao, Xun Jin
Journal: Theranostics (2024)

Rationale:The heterogeneity of tumor cells within the glioblastoma (GBM) microenvironment presents a complex challenge in curbing GBM progression.Understanding the specific mechanisms of interaction between different GBM cell subclusters and non-tumor cells is crucial.Methods: In this study, we utilized a comprehensive approach integrating glioma single-cell and spatial transcriptomics.This allowed us to examine the molecular interactions and spatial localization within GBM, focusing on a specific tumor cell subcluster, GBM subcluster 6, and M2-type tumor-associated macrophages (M2 TAMs).Results: Our analysis revealed a significant correlation between a specific tumor cell subcluster, GBM cluster 6, and M2-type TAMs.Further in vitro and in vivo experiments demonstrated the specific regulatory role of the CEBPB transcriptional network in GBM subcluster 6, which governs its tumorigenicity, recruitment of M2 TAMs, and polarization.This regulation involves molecules such as MCP1 for macrophage recruitment and the SPP1-Integrin αvβ1-Akt signaling pathway for M2 polarization.Conclusion: Our findings not only deepen our understanding of the formation of M2 TAMs, particularly highlighting the differential roles played by heterogeneous cells within GBM in this process, but also provided new insights for effectively controlling the malignant progression of GBM.
Lens autophagy protein ATG16L1: a potential target for cataract treatment
Authors: Yilei Cui, Xiaoning Yu, Jing Bao, Xiyuan Ping, Silu Shi, Yuxin Huang, Qichuan Yin, Hao Yang, Ruoqi Chen, Ke Yao, Xiangjun Chen, Xingchao Shentu
Journal: Theranostics (2024)

Cataract is the leading cause of blindness and low vision worldwide, yet its pathological mechanism is not fully understood. Although macroautophagy/autophagy is recognized as essential for lens homeostasis and has shown potential in alleviating cataracts, its precise mechanism remains unclear. Uncovering the molecular details of autophagy in the lens could provide targeted therapeutic interventions alongside surgery.
Osteoblast-specific down-regulation of NLRP3 inflammasome by aptamer-functionalized liposome nanoparticles improves bone quality in postmenopausal osteoporosis rats
Authors: Lijun Xu, Jie Zhu, Lingjun Rong, Huinan Yang, Bin Wang, Shuai Lu, Lingxiao Zhang, Fuyi Li, Shihua Yang, Zhifang Wang, Chong Li, Xiao Hu, Ruoyun Liu, Lili Zheng, Hongjian Liu, Haohao Zhang, Yanling Liu, Di Zhao, Shuiying Zhao, Lun Zhang, Yingbo Jia, Shiyu Liang, Zhikang Guo, Xixiu Xie, Ruitian Liu, Lixia Zhang
Journal: Theranostics (2024)

NLRP3 inflammasome is critical in the development and progression of many metabolic diseases driven by chronic inflammation, but its effect on the pathology of postmenopausal osteoporosis (PMOP) remains poorly understood.
A Pan-Cancer Patient-Derived Xenograft Histology Image Repository with Genomic and Pathologic Annotations Enables Deep Learning Analysis
Authors: Brian S. White, Xing Yi Woo, Soner Koc, Todd Sheridan, Steven B. Neuhauser, Shidan Wang, Yvonne A. Evrard, Li Chen, Ali Foroughi pour, John D. Landua, R. Jay Mashl, Sherri R. Davies, Bingliang Fang, Maria Gabriela Raso, Kurt W. Evans, Matthew H. Bailey, Yeqing Chen, Min Xiao, Jill C. Rubinstein, Brian J. Sanderson, Michael W. Lloyd, Sergii Domanskyi, Lacey E. Dobrolecki, Maihi Fujita, Junya Fujimoto, Guanghua Xiao, Ryan C. Fields, Jacqueline L. Mudd, Xiaowei Xu, Melinda G. Hollingshead, Shahanawaz Jiwani, Saul Acevedo, Brandi N. Davis-Dusenbery, Peter N. Robinson, Jeffrey A. Moscow, James H. Doroshow, Nicholas Mitsiades, Salma Kaochar, Chong-xian Pan, Luis G. Carvajal-Carmona, Alana L. Welm, Bryan E. Welm, Ramaswamy Govindan, Shunqiang Li, Michael A. Davies, Jack A. Roth, Funda Meric-Bernstam, Yang Xie, Meenhard Herlyn, Li Ding, Michael T. Lewis, Carol J. Bult, Dennis A. Dean, Jeffrey H. Chuang
Journal: Cancer Research (2024)

Patient-derived xenografts (PDX) model human intra- and intertumoral heterogeneity in the context of the intact tissue of immunocompromised mice. Histologic imaging via hematoxylin and eosin (H&E) staining is routinely performed on PDX samples, which could be harnessed for computational analysis. Prior studies of large clinical H&E image repositories have shown that deep learning analysis can identify intercellular and morphologic signals correlated with disease phenotype and therapeutic response. In this study, we developed an extensive, pan-cancer repository of >1,000 PDX and paired parental tumor H&E images. These images, curated from the PDX Development and Trial Centers Research Network Consortium, had a range of associated genomic and transcriptomic data, clinical metadata, pathologic assessments of cell composition, and, in several cases, detailed pathologic annotations of neoplastic, stromal, and necrotic regions. The amenability of these images to deep learning was highlighted through three applications: (i) development of a classifier for neoplastic, stromal, and necrotic regions; (ii) development of a predictor of xenograft-transplant lymphoproliferative disorder; and (iii) application of a published predictor of microsatellite instability. Together, this PDX Development and Trial Centers Research Network image repository provides a valuable resource for controlled digital pathology analysis, both for the evaluation of technical issues and for the development of computational image-based methods that make clinical predictions based on PDX treatment studies. Significance: A pan-cancer repository of >1,000 patient-derived xenograft hematoxylin and eosin-stained images will facilitate cancer biology investigations through histopathologic analysis and contributes important model system data that expand existing human histology repositories.
A Tetravalent Bispecific Antibody Selectively Inhibits Diverse FGFR3 Oncogenic Variants
Authors: Yan Yang, Avvaru N. Suhasini, Zaoli Jiang, Nina Liu, Michael Rosconi, Bojie Zhang, Yinyin Li, Drew Dudgeon, Changhyun Seong, Steven Kim, Ashique Rafique, Tammy Huang, Sangram Bhosle, Pamela Krueger, Erica Ullman, William Olson, John C. Lin, Yang Shen, Christopher Daly
Journal: Cancer Research (2024)

Abstract The receptor tyrosine kinase FGFR3 is frequently mutated in bladder cancer and is a validated therapeutic target. Although pan-FGFR tyrosine kinase inhibitors (TKI) have shown clinical efficacy, toxicity and acquired resistance limit the benefit of these agents. While antibody-based therapeutics can offer superior selectivity than TKIs, conventional ligand-blocking antibodies are usually ineffective inhibitors of constitutively active receptor tyrosine kinases. Furthermore, the existence of multiple oncogenic variants of FGFR3 presents an additional challenge for antibody-mediated blockade. Here, we developed a tetravalent FGFR3×FGFR3 bispecific antibody that inhibited FGFR3 point mutants and fusion proteins more effectively than any of the conventional FGFR3 antibodies that we produced. Each arm of the bispecific antibody contacted two distinct epitopes of FGFR3 through a cis mode of binding. The antibody blocked dimerization of the most common FGFR3 oncogenic variant (S249C extracellular domain mutation) and inhibited the function of FGFR3 variants that are resistant to pan-FGFR TKIs. The antibody was highly effective in suppressing growth of FGFR3-driven tumor models, providing efficacy comparable to that of the FDA-approved TKI erdafitinib. Thus, this bispecific antibody may provide an effective approach for broad and highly selective inhibition of oncogenic FGFR3 variants. Significance: Development of a bispecific antibody that broadly inhibits gain-of-function FGFR3 variants provides a therapeutic strategy to target tumors with oncogenic FGFR3 point mutations and fusions, a particularly difficult case for antibody blockade.
Pediatric sex estimation using AI-enabled ECG analysis: influence of pubertal development
Authors: Donnchadh O’Sullivan, Scott Anjewierden, Grace Greason, Itzhak Zachi Attia, Francisco Lopez-Jimenez, Paul A. Friedman, Peter Noseworthy, Jason Anderson, Anthony Kashou, Samuel J. Asirvatham, Benjamin W. Eidem, Jonathan N. Johnson, Talha Niaz, Malini Madhavan
Journal: npj Digital Medicine (2024)

Abstract AI-enabled ECGs have previously been shown to accurately predict patient sex in adults and correlate with sex hormone levels. We aimed to test the ability of AI-enabled ECGs to predict sex in the pediatric population and study the influence of pubertal development. AI-enabled ECG models were created using a convolutional neural network trained on pediatric 10-second, 12-lead ECGs. The first model was trained de novo using pediatric data. The second model used transfer learning from a previously validated adult data-derived algorithm. We analyzed the first ECG from 90,133 unique pediatric patients (aged ≤18 years) recorded between 1987–2022, and divided the cohort into training, validation, and testing datasets. Subgroup analysis was performed on prepubertal (0–7 years), peripubertal (8–14 years), and postpubertal (15–18 years) patients. The cohort was 46.7% male, with 21,678 prepubertal, 26,740 peripubertal, and 41,715 postpubertal children. The de novo pediatric model demonstrated 81% accuracy and an area under the curve (AUC) of 0.91. Model sensitivity was 0.79, specificity was 0.83, positive predicted value was 0.84, and the negative predicted value was 0.78, for the entire test cohort. The model’s discriminatory ability was highest in postpubertal (AUC = 0.98), lower in the peripubertal age group (AUC = 0.91), and poor in the prepubertal age group (AUC = 0.67). There was no significant performance difference observed between the transfer learning and de novo models. AI-enabled interpretation of ECG can estimate sex in peripubertal and postpubertal children with high accuracy.
Adhesion GPCR ADGRE2 Maintains Proteostasis to Promote Progression in Acute Myeloid Leukemia
Authors: Deyu Huang, Zebin Yu, Huan Lu, Penglei Jiang, Xinyue Qian, Yingli Han, Pengxu Qian
Journal: Cancer Research (2024)

Acute myeloid leukemia (AML) is an aggressive and heterogeneous hematologic malignancy. In elderly patients, AML incidence is high and has a poor prognosis due to a lack of effective therapies. G protein-coupled receptors (GPCR) play integral roles in physiologic processes and human diseases. Particularly, one third of adhesion GPCRs, the second largest group of GPCRs, are highly expressed in hematopoietic stem and progenitor cells or lineage cells. Here, we investigate the role of adhesion GPCRs in AML and whether they could be harnessed as antileukemia targets. Systematic screening of the impact of adhesion GPCRs on AML functionality by bioinformatic and functional analyses revealed high expression of ADGRE2 in AML, particularly in leukemic stem cells, which is associated with poor patient outcomes. Silencing ADGRE2 not only exerts antileukemic effects in AML cell lines and cells derived from patients with AML in vitro, but also delays AML progression in xenograft models in vivo. Mechanistically, ADGRE2 activates phospholipase Cβ/protein kinase C/MEK/ERK signaling to enhance the expression of AP1 and transcriptionally drive the expression of DUSP1, a protein phosphatase. DUSP1 dephosphorylates Ser16 in the J-domain of the co-chaperone DNAJB1, which facilitates the DNAJB1-HSP70 interaction and maintenance of proteostasis in AML. Finally, combined inhibition of MEK, AP1, and DUSP1 exhibits robust therapeutic efficacy in AML xenograft mouse models. Collectively, this study deciphers the roles and mechanisms of ADGRE2 in AML and provides a promising therapeutic strategy for treating AML. Significance: Increased expression of the adhesion GPCR member ADGRE2 in AML supports leukemia stem cell self-renewal and leukemogenesis by modulating proteostasis via an MEK/AP1/DUSP1 axis, which can be targeted to suppress AML progression.
The Warburg Effect Revisited through Blood and Electron Flow
Authors: Yahui Wang, Chi V. Dang
Journal: Cancer Research (2024)

Abstract The Warburg effect describes the propensity of many cancers to consume glucose avidly and convert it to lactate in the presence of oxygen. The benefit of the Warburg effect on cancer cells remains enigmatic, particularly because extracellular disposal of incompletely oxidized lactate is wasteful. However, lactate is not discarded from the body, but rather recycled as pyruvate for metabolism through the tricarboxylic acid cycle in oxidative tissues and cells. Hence, tissue and interorgan metabolism play important roles in tumor metabolism. The production of tumor lactate to be recycled elsewhere parallels the Cori cycle, in which lactate produced by muscle activity is shuttled to the liver, where it is converted to pyruvate and subsequently stored as glucose moieties in glycogen. This perspective will consider this organismal contextwhile discussing how glucose is used in tumors. We highlight several key articles published decades ago in Cancer Research that are foundational to our current understanding of cancer biology and metabolism.
Synthetic high-density lipoprotein (sHDL): a bioinspired nanotherapeutics for managing periapical bone inflammation
Authors: Renan Dal-Fabbro, Minzhi Yu, Ling Mei, Hajime Sasaki, Anna Schwendeman, Marco C. Bottino
Journal: International Journal of Oral Science (2024)

Abstract Apical periodontitis (AP) is a dental-driven condition caused by pathogens and their toxins infecting the inner portion of the tooth ( i.e ., dental pulp tissue), resulting in inflammation and apical bone resorption affecting 50% of the worldwide population, with more than 15 million root canals performed annually in the United States. Current treatment involves cleaning and decontaminating the infected tissue with chemo-mechanical approaches and materials introduced years ago, such as calcium hydroxide, zinc oxide–eugenol, or even formalin products. Here, we present, for the first time, a nanotherapeutics based on using synthetic high-density lipoprotein (sHDL) as an innovative and safe strategy to manage dental bone inflammation. sHDL application in concentrations ranging from 25 µg to 100 µg/mL decreases nuclear factor Kappa B (NF-κB) activation promoted by an inflammatory stimulus (lipopolysaccharide, LPS). Moreover, sHDL at 500 µg/mL concentration markedly decreases in vitro osteoclastogenesis ( P &lt; 0.001), and inhibits IL-1α ( P = 0.027), TNF-α ( P = 0.004), and IL-6 ( P &lt; 0.001) production in an inflammatory state. Notably, sHDL strongly dampens the Toll-Like Receptor signaling pathway facing LPS stimulation, mainly by downregulating at least 3-fold the pro-inflammatory genes, such as Il1b , Il1a , Il6 , Ptgs2 , and Tnf . In vivo, the lipoprotein nanoparticle applied after NaOCl reduced bone resorption volume to (1.3 ± 0.05) mm 3 and attenuated the inflammatory reaction after treatment to (1 090 ± 184) cells compared to non-treated animals that had (2.9 ± 0.6) mm 3 ( P = 0.012 3) and (2 443 ± 931) cells ( P = 0.004), thus highlighting its promising clinical potential as an alternative therapeutic for managing dental bone inflammation.
Optimized rAAV8 targeting acinar KLF4 ameliorates fibrosis in chronic pancreatitis via exosomes-enriched let-7s suppressing pancreatic stellate cells activation
Authors: Yating Zhao, Yongpu Feng, Fengyuan Sun, Lei Li, Jiayu Chen, Yingxiao Song, Wenbo Zhu, Xiulin Hu, Zhaoshen Li, Fanyang Kong, Yiqi Du, Xiangyu Kong
Journal: Molecular Therapy (2024)
How to manage adult patients with malaria in the non-endemic setting
Authors: Spinello Antinori, Andrea Giacomelli, Giacomo Casalini, Anna Lisa Ridolfo
Journal: Clinical Microbiology and Infection (2024)

BackgroundThe diagnosis and management of malaria in non-endemic countries presents a continuing challenge. Plasmodium falciparum, which is capable to rapidly induce severe and life-threatening multiorgan disease, is the species most frequently diagnosed in Europe and North America.ObjectivesTo summarise the more relevant diagnostic findings and clinical features of malaria observed in non-endemic settings and to provide an up-date of the key management decision points using three illustrative clinical scenarios of uncomplicated and severe malaria.SourcesThe discussion is based on relevant literature search spanning the last twenty years. Recommendations are based on available clinical guidelines including those of the World Health Organization (WHO), on observational studies conducted in non-endemic settings and, when available, with extrapolation from randomised studies from malaria endemic settings.ContentThe following topics are covered: diagnosis, including the use of molecular biology; clinical characteristics; management with specific focus on complicated (severe) and uncomplicated malaria and on areas of resistance to available antimalarial drugs.ImplicationsMalaria imported to non-endemic settings, especially Plasmodium falciparum malaria, is sometimes initially overlooked and the delayed diagnosis is responsible every year of preventable deaths. This review aims to raise awareness of malaria outside endemic countries and to provide clinicians with a practical guide for efficient diagnosis and targeted therapy to the different species involved.
Correction: Monoclonal proteinuria predicts progression risk in asymptomatic multiple myeloma with a free light chain ratio ≥100
Authors: Alissa Visram, S. Vincent Rajkumar, Prashant Kapoor, Angela Dispenzieri, Martha Q. Lacy, Morie A. Gertz, Francis K. Buadi, Suzanne R. Hayman, David Dingli, Taxiarchis Kourelis, Wilson Gonsalves, Rahma Warsame, Eli Muchtar, Nelson Leung, Robert A. Kyle, Shaji K. Kumar
Journal: Leukemia (2024)
Retinal Tear and Retinal Detachment after Cataract Surgery in Eyes with a Previous History of Treated Phakic Retinal Tears
Authors: Bita Momenaei, Andrew Zhou, Adina S. Kazan, Taku Wakabayashi, Anthony Obeid, Michael Morano, M. Ali Khan, David Xu, Ajay E. Kuriyan, Yoshihiro Yonekawa, Jason Hsu, Allen C. Ho
Journal: Ophthalmology (2024)