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Current status of the preclinical evaluation of alternating electric fields as a form of cancer therapy

Bioelectrochemistry 2023年 149卷 108287页

作者： Pohling, Christoph Nguyen, Ha Chang, Edwin Schubert, Keith E. Nie, Ying Bashkirov, Vladimir Yamamoto, Vicky Zeng, Yuping Stupp, Roger Schulte, Reinhard W. Patel, Chirag B. Division of Biomedical Engineering Sciences Loma Linda University School of Medicine Loma LindaCA92350 United States Department of Electrical and Computer Engineering Baylor University WacoTX76798 United States Molecular Imaging Program at Stanford Department of Radiology Stanford University School of Medicine StanfordCA94305 United States Department of Neurosurgery Loma Linda University School of Medicine Loma LindaCA92350 United States Norris Comprehensive Cancer Center University of Southern California Keck School of Medicine Los AngelesCA90033 United States Department of Electrical and Computer Engineering University of Delaware NewarkDE19716 United States Department of Neurosurgery Department of Neurology Division of Neuro-OncologyDepartment of Medicine Division of Hematology/Oncology Northwestern University Feinberg School of Medicine ChicagoIL60611 United States Department of Neuro-Oncology The University of Texas MD Anderson Cancer Center HoustonTX77030 United States Neuroscience Graduate Program The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences HoustonTX77030 United States Cancer Biology Graduate Program The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences HoustonTX77030 United States

Exposing cancer cells to alternating electric fields of 100-300 kHz frequency and 1-4 V/cm strength has been shown to significantly reduce cancer growth in cell culture and in human patients. This form of anti-cancer therapy is more commonly referred to as tumor treating fields (TTFields), a novel treatment modality that has been approved by the U.S. Food and Drug Administration for use in patients with glioblastoma and malignant pleural mesothelioma. Pivotal trials in other solid organ cancer trials are underway. In regards to overall survival, TTFields alone is comparable to chemotherapy alone in recurrent glioblastoma. However, when combined with adjuvant chemotherapy, TTFields prolong median survival by 4.9 months in newly-diagnosed glioblastoma. TTFields hold promise as a therapeutic approach to numerous solid organ cancers. This review summarizes the current status of TTFields research at the preclinical level, highlighting recent aspects of a relatively complex working hypothesis. In addition, we point out the gaps between limited preclinical in vivo studies and the available clinical data. To date, no customized system for TTFields delivery in rodent models of glioblastoma has been presented. We aim to motivate the expansion of TTFields preclinical research and facilitate the availability of suitable hardware, to ultimately improve outcomes in patients with cancer. © 2022 The Authors

关键词： Tumors

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Integrating spatially-resolved transcriptomics data across tissues and individuals: challenges and opportunities

arXiv

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arXiv 2024年

作者： Guo, Boyi Ling, Wodan Kwon, Sang Ho Panwar, Pratibha Ghazanfar, Shila Martinowich, Keri Hicks, Stephanie C. Department of Biostatistics Johns Hopkins Bloomberg School of Public Health BaltimoreMD United States Division of Biostatistics Department of Population Health Sciences Weill Cornell Medicine NY United States Lieber Institute for Brain Development Johns Hopkins Medical Campus BaltimoreMD United States Solomon H. Snyder Department of Neuroscience Johns Hopkins School of Medicine BaltimoreMD United States Biochemistry Cellular and Molecular Biology Graduate Program Johns Hopkins School of Medicine BaltimoreMD United States School of Mathematics and Statistics The University of Sydney NSW2006 Australia Sydney Precision Data Science Centre University of Sydney NSW2006 Australia Charles Perkins Centre The University of Sydney NSW2006 Australia Department of Psychiatry and Behavioral Sciences Johns Hopkins School of Medicine BaltimoreMD United States Johns Hopkins Kavli Neuroscience Discovery Institute BaltimoreMD United States Department of Biomedical Engineering Johns Hopkins University BaltimoreMD United States Center for Computational Biology Johns Hopkins University BaltimoreMD United States Malone Center for Engineering in Healthcare Johns Hopkins University BaltimoreMD United States

Advances in spatially-resolved transcriptomics (SRT) technologies have propelled the development of new computational analysis methods to unlock biological insights. As the cost of generating these data decreases, these technologies provide an exciting opportunity to create large-scale atlases that integrate SRT data across multiple tissues, individuals, species, or phenotypes to perform population-level analyses. Here, we describe unique challenges of varying spatial resolutions in SRT data, as well as highlight the opportunities for standardized preprocessing methods along with computational algorithms amenable to atlas-scale datasets leading to improved sensitivity and reproducibility in the future. © 2024, CC BY-NC-ND.

关键词： Biotic

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DNA-damage-associated protein co-expression network in cardiomyocytes informs on tolerance to genetic variation and disease

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iScience 2025年第5期28卷 112474页

作者： Johnson, Omar Darrel Paul, Sayan Gutiérrez, José Angel Russell, William Kent Ward, Michelle Claire Biochemistry Cellular and Molecular Biology Graduate Program University of Texas Medical Branch Galveston 77555 TX United States MD-PhD Combined Degree Program University of Texas Medical Branch Galveston 77555 TX United States Department of Biochemistry and Molecular Biology University of Texas Medical Branch Galveston 77555 TX United States

Cardiovascular disease (CVD) is associated with genetic variants and environmental factors. A consequence of multiple risk factors is DNA damage. To examine how DNA damage influences the cardiomyocyte proteome and its relationship to CVD risk, we treated human induced pluripotent stem cell (iPSC)-derived cardiomyocytes with the DNA-damaging agent doxorubicin (DOX). A network constructed from 4,178 proteins reveals 12 co-expressed modules with 403 hub proteins. Five modules correlate with DOX and associate with RNA processing, chromatin regulation, and metabolism. DOX-correlated hub proteins are depleted for proteins that vary in expression across individuals due to genetic variation but are enriched for proteins encoded by loss-of-function intolerant genes. While not enriched for known CVD risk proteins, DOX-correlated hub proteins are enriched for the physical protein interactors of CVD risk proteins. These data demonstrate that protein connectivity in DNA-damage-associated modules influences the tolerance to genetic variation and supports the use of dynamic networks to explore complex traits. © 2025 The Author(s)

关键词： Integrative aspects of cell biology Molecular network Proteomics

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Genetically Engineered Mouse Models for Alzheimer Disease and Frontotemporal Dementia: New Insights from Single-Cell and Spatial Transcriptomics

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The American journal of pathology 2024年

作者： Yuanpu Chiu Shangzhou Xia Haowen Qiao Zhen Zhao Department of Physiology and Biophysics Center for Neurodegeneration and Regeneration Zilkha Neurogenetic Institute Keck School of Medicine University of Southern California Los Angeles California Neuromedicine PhD Program Programs in Biomedical and Biological Sciences (PIBBS) Keck School of Medicine University of Southern California Los Angeles California. Neuroscience Graduate Program University of Southern California Los Angeles California. Department of Physiology and Biophysics Center for Neurodegeneration and Regeneration Zilkha Neurogenetic Institute Keck School of Medicine University of Southern California Los Angeles California. Neuromedicine PhD Program Programs in Biomedical and Biological Sciences (PIBBS) Keck School of Medicine University of Southern California Los Angeles California Neuroscience Graduate Program University of Southern California Los Angeles California. Electronic address: zzhao@usc.edu.

Neurodegenerative diseases, including Alzheimer disease, frontotemporal dementia, Parkinson disease, Huntington disease, and amyotrophic lateral sclerosis, are often casually linked to protein aggregation and inclusion. As the origins of those proteinopathies have been biochemically traced and genetically mapped, genetically engineered animal models carrying the specific mutations or variants are widely used for investigating the etiology of these diseases, as well as for testing potential therapeutics. This article focuses on the mouse models of Alzheimer disease and closely related frontotemporal dementia, particularly the ones that have provided most valuable knowledge, or are in a trajectory of doing so. More importantly, some of the major findings from these models are summarized, based on the recent single-cell transcriptomics, multiomics, and spatial transcriptomics studies. While no model is perfect, it is hoped that the new insights from these models and the practical use of these models will continue to help to establish a path forward.

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Data Processing of Functional Optical Microscopy for neuroscience

arXiv

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arXiv 2022年

作者： Benisty, Hadas Song, Alexander Mishne, Gal Charles, Adam S. Yale Neuroscience New HavenCT06510 United States Max Planck Institute for Intelligent Systems Stuttgart Germany Halıcıoğlu Data Science Institute Department of Electrical and Computer Engineering Neurosciences Graduate Program UC San Diego 9500 Gilman Drive La Jolla CA92093 United States Department of Biomedical Engineering Kavli Neuroscience Discovery Institute Center for Imaging Science Department of Neuroscience Mathematical Institute for Data Science Johns Hopkins University BaltimoreMD21287 United States

Functional optical imaging in neuroscience is rapidly growing with the development of new optical systems and fluorescence indicators. To realize the potential of these massive spatiotemporal datasets for relating neuronal activity to behavior and stimuli and uncovering local circuits in the brain, accurate automated processing is increasingly essential. In this review, we cover recent computational developments in the full data processing pipeline of functional optical microscopy for neuroscience data and discuss ongoing and emerging challenges. © 2022, CC BY-NC-ND.

关键词： Fluorescence microscopy

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Inflammatory Mediators in Glioma Microenvironment Play a Dual Role in Gliomagenesis and Mesenchymal Stem Cell Homing: Implication for Cellular Therapy

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Mayo Clinic Proceedings: Innovations, Quality and Outcomes 2020年第4期4卷 443-459页

作者： Al-kharboosh, Rawan ReFaey, Karim Lara-Velazquez, Montserrat Grewal, Sanjeet S. Imitola, Jaime Quiñones-Hinojosa, Alfredo Department of Neurosurgery Mayo Clinic Jacksonville FL United States Mayo Clinic College of Medicine and Science Mayo Clinic Graduate School of Biomedical Sciences (Neuroscience Track) Regenerative Sciences Training Program Mayo Clinic Rochester MN United States Department of Neurology Research Division of Multiple Sclerosis and Translational Neuroimmunology UConn School of Medicine Farmington CT United States Plan of Combined Studies in Medicine (MD/PhD) National Autonomous University of Mexico Mexico City

Glioblastoma is the most aggressive malignant primary brain tumor, with a dismal prognosis and a devastating overall survival. Despite aggressive surgical resection and adjuvant treatment, average survival remains approximately 14.6 months. The brain tumor microenvironment is heterogeneous, comprising multiple populations of tumor, stromal, and immune cells. Tumor cells evade the immune system by suppressing several immune functions to enable survival. Gliomas release immunosuppressive and tumor-supportive soluble factors into the microenvironment, leading to accelerated cancer proliferation, invasion, and immune escape. Mesenchymal stem cells (MSCs) isolated from bone marrow, adipose tissue, or umbilical cord are a promising tool for cell-based therapies. One crucial mechanism mediating the therapeutic outcomes often seen in MSC application is their tropism to sites of injury. Furthermore, MSCs interact with host immune cells to regulate the inflammatory response, and data points to the possibility of using MSCs to achieve immunomodulation in solid tumors. Interleukin 1β, interleukin 6, tumor necrosis factor α, transforming growth factor β, and stromal cell–derived factor 1 are notably up-regulated in glioblastoma and dually promote immune and MSC trafficking. Mesenchymal stem cells have widely been regarded as hypoimmunogenic, enabling this cell-based administration across major histocompatibility barriers. In this review, we will highlight (1) the bidirectional communication of glioma cells and tumor-associated immune cells, (2) the inflammatory mediators enabling leukocytes and transplantable MSC migration, and (3) review preclinical and human clinical trials using MSCs as delivery vehicles. Mesenchymal stem cells possess innate abilities to migrate great distances, cross the blood-brain barrier, and communicate with surrounding cells, all of which make them desirable “Trojan horses” for brain cancer therapy. © 2020 Mayo Foundation for Medical Education and Rese

关键词： AMSC adipose tissue–derived mesenchymal stem cell BBB blood-brain barrier BMSC bone marrow–derived mesenchymal stem cell CED convection-enhanced delivery DC dendritic cell EGFRvIII EGFR variant III 5-FC 5-fluorocytosine GBM glioblastoma GSC glioma stem cell IFN interferon IL interleukin mdSC myeloid-derived suppressor cell MHC major histocompatibility complex MSC mesenchymal stem cell NSC neural stem cell TAM tumor-associated macrophage TGF transforming growth factor TNF tumor necrosis factor UC-MSC umbilical cord MSC

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Symmetries and synchronization from whole-neural activity in C. elegans connectome: Integration of functional and structural networks

arXiv

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arXiv 2024年

作者： Avila, Bryant Augusto, Pedro Phillips, David Gili, Tommaso Zimmer, Manuel Makse, Hernán A. Levich Institute and Physics Department City College of New York New YorkNY10031 United States Vienna Austria Vienna Biocenter PhD Program Doctoral School the University of Vienna Medical University of Vienna Vienna Austria Mechanical Engineering Department University of New Mexico AlbuquerqueNM87131 United States Networks Unit IMT Scuola Alti Studi Lucca Piazza San Francesco 15 Lucca55100 Italy Department of Radiology Neuroradiology Service Memorial Sloan Kettering Cancer Center New YorkNY10065 United States CUNY Neuroscience Graduate Center City University of New York New YorkNY10031 United States

Understanding the dynamical behavior of complex systems from their underlying network architectures is a long-standing question in complexity theory. Therefore, many metrics have been devised to extract network features like motifs, centrality, and modularity measures. It has previously been proposed that network symmetries are of particular importance since they are expected to underly the synchronization of a system’s units, which is ubiquitously observed in nervous system activity patterns. However, perfectly symmetrical structures are difficult to assess in noisy measurements of biological systems, like neuronal connectomes. Here, we devise a principled method to infer network symmetries from combined connectome and neuronal activity data. Using nervous system-wide population activity recordings of the *** backward locomotor system, we infer structures in the connectome called fibration symmetries, which can explain which group of neurons synchronize their activity. Our analysis suggests functional building blocks in the animal’s motor periphery, providing new testable hypotheses on how descending interneuron circuits communicate with the motor periphery to control behavior. Our approach opens a new door to exploring the structure-function relations in other complex systems, like the nervous systems of larger animals. © 2024, CC BY.

关键词： Synchronization

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06O NLRP3 inflammasome activation and altered mitophagy are key pathways in inclusion body myositis

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Neuromuscular Disorders 2024年 43卷 104441.10-104441.10页

作者： Naddaf, E. Nguyen, T. Watzlawik, J. Gao, H. Hou, X. Fiesel, F. Mandrekar, J. Kokesh, E. Harmsen, W. Lanza, I. Springer, W. Trushina, E. Department of Neurology Mayo Clinic Rochester USA Department of Neuroscience Mayo Clinic Jacksonville USA Department of Molecular Pharmacology and Experimental Therapeutics Mayo Clinic Rochester USA Neuroscience PhD Program Mayo Clinic Graduate School of Biomedical Sciences Jacksonville USA Department of Quantitative Health Sciences Mayo Clinic Rochester USA Division of Endocrinology and Metabolism Mayo Clinic Rochester USA

Inclusion body myositis (IBM) is the most prevalent muscle disease in adults for which no current treatment exists. The pathogenesis of IBM remains poorly defined. Inflammation and mitochondrial dysfunction are the most common histopathological findings. In this study, we aimed to explore the interplay between inflammation and mitochondrial dysfunction in IBM patients. We included 38 IBM patients and 22 age- and sex-matched controls without myopathy. Bulk RNA sequencing, Meso Scale Discovery ELISA, western blotting, histochemistry and immunohistochemistry were performed on frozen muscle samples from the study participants. We demonstrated activation of the NLRP3 inflammasome in IBM muscle samples, with the NLRP3 inflammasome pathway being the most upregulated pathway. On muscle histopathology, there was increased NRLP3 immunoreactivity in both inflammatory cells and muscle fibers. Mitophagy is critical for removing damaged mitochondria and preventing the formation of a vicious cycle of mitochondrial dysfunction—NLRP3 activation. In the IBM muscle samples, we showed altered mitophagy with elevated levels of p-S65-Ubiquitin, a mitophagy marker. Furthermore, p-S65-Ubiquitin aggregates accumulated in muscle fibers that were mostly type 2 and devoid of cytochrome-c-oxidase reactivity. Type 2 muscle fibers are known to be more prone to mitochondrial dysfunction. NLRP3 RNA levels correlated with p-S65-Ubiquitin levels. NLRP3 inflammasome is activated in IBM, along with altered mitophagy, potentially forming a self-sustaining vicious cycle. These findings could have potential therapeutic significance.

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CellBiAge: Improved single-cell age classification using data binarization

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Cell Reports 2023年第12期42卷 113500页

作者： Yu, Doudou Li, Manlin Linghu, Guanjie Hu, Yihuan Hajdarovic, Kaitlyn H. Wang, An Singh, Ritambhara Webb, Ashley E. Molecular Biology Cell Biology and Biochemistry Graduate Program Brown University Providence 02912 RI United States Data Science Institute Brown University Providence 02912 RI United States Neuroscience Graduate Program Brown University Providence 02912 RI United States Department of Applied Mathematics & Statistics Johns Hopkins University Baltimore 21218 MD United States Department of Computer Science Brown University Providence 02912 RI United States Center for Computational Molecular Biology Brown University Providence 02912 RI United States Department of Molecular Biology Cell Biology and Biochemistry Brown University Providence 02912 RI United States Center on the Biology of Aging Brown University Providence 02912 RI United States Carney Institute for Brain Science Brown University Providence 02912 RI United States Center for Translational Neuroscience Brown University Providence 02912 RI United States

Aging is a major risk factor for many diseases. Accurate methods for predicting age in specific cell types are essential to understand the heterogeneity of aging and to assess rejuvenation strategies. However, classifying organismal age at single-cell resolution using transcriptomics is challenging due to sparsity and noise. Here, we developed CellBiAge, a robust and easy-to-implement machine learning pipeline, to classify the age of single cells in the mouse brain using single-cell transcriptomics. We show that binarization of gene expression values for the top highly variable genes significantly improved test performance across different models, techniques, sexes, and brain regions, with potential age-related genes identified for model prediction. Additionally, we demonstrate CellBiAge's ability to capture exercise-induced rejuvenation in neural stem cells. This study provides a broadly applicable approach for robust classification of organismal age of single cells in the mouse brain, which may aid in understanding the aging process and evaluating rejuvenation methods. © 2023 The Authors

关键词： aging brain CP: Cell biology hypothalamus machine learning single-cell RNA-seq

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CuO NWs boosted triboelectric microfluidic nanosensor functionalized by collagen-protein interactions for real-time platelet count monitoring

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Chemical Engineering Journal 2024年 490卷

作者： Lin, Jia-Cheng Kaswan, Kuldeep Chatterjee, Subhodeep Wu, Yu-Wen Kumar Sharma, Manish Ranjan, Ashok Roy Barman, Snigdha Lin, Yu-Zih Burnouf, Thierry Boireau, Wilfrid Lu, Ming-Yen Tu, Yong-Kwang Su, I-Chang Wu, Ping-Hsiu Lin, Zong-Hong Fan, Yu-Jui School of Biomedical Engineering Taipei Medical University Taipei11031 Taiwan Taipei Neuroscience Institute Taipei Medical University Taipei11031 Taiwan Department of Biomedical Engineering National Taiwan University Taipei11031 Taiwan International Intercollegiate PhD Program National Tsing Hua University Hsinchu30013 Taiwan Department of Power Mechanical Engineering National Tsing Hua University Hsinchu30013 Taiwan Graduate Institute of Biomedical Materials and Tissue Engineering Taipei Medical University Taipei11031 Taiwan Department of Material Science and Engineering National Tsing Hua University Hsinchu30013 Taiwan Institute of Biomedical Engineering National Tsing Hua University Hsinchu30013 Taiwan International PhD Program in Biomedical Engineering Taipei Medical University Taipei11031 Taiwan Université de Franche-Comté CNRS Institut FEMTO-ST BesançonF-25030 France Department of Neurosurgery Shuang Ho Hospital Taipei Medical University New Taipei City23561 Taiwan Department of Surgery School of Medicine College of Medicine Taipei Medical University Taipei11031 Taiwan Department of Radiology School of Medicine College of Medicine Taipei Medical University Taipei11031 Taiwan Department of Radiation Oncology Taipei Medical University Hospital Taipei11031 Taiwan Center for Precision Health and Quantitative Sciences Taipei Medical University Hospital Taipei 11031 Taiwan

Blood platelet count significantly affects the development of severe conditions like myocardial infarction, peripheral arterial ischemia, respiratory compromise, stroke, diabetes, coronavirus disease 2019 (COVID-19), along with chemotherapy patients and those suffering cardiovascular diseases (CVDs). These conditions necessitate frequent monitoring of platelet counts to guide diagnostic and therapeutic decisions. However, existing techniques are relatively time-consuming, lack of accuracy and require precise operation. The emergence of these severe diseases underscored the need to develop advanced platelet count-monitoring techniques which are rapid, highly precise, and conveniently portable for point-of-care applications. In this study, we emphasized the development of a triboelectric microfluidic nanosensor (TMNS) for platelet quantification through the assessment of flow resistance. The functionality of TMNS device is based on immobilization of platelets on a collagen layer coated inside a microfluidic channel. The triboelectric voltage output is measured as a detection signal of the flow resistance and is enhanced by incorporating high surface area copper oxide nanowires (CuO NWs) on the interior of copper tubes. These copper tubes serve as terminal electrodes and for flow guiding. The flow resistance of plasma solutions is elevated when the platelet concentration increases due to heightened adherence of platelets onto the collagen layer. Variations in flow resistance induce alterations in contact electrification, causing changes in output voltage at load terminals. Fine-tuning of the TMNS device was achieved by optimizing the channel width and length, flowing liquid viscosity, and voltage measurement technique. Platelet quantification sensing data were acquired through the combination of platelet-rich plasma (PRP) and platelet-poor plasma (PPP) solutions. The described device exhibits promising capabilities for platelet-count monitoring in whole-blood samples c

关键词： Copper oxides

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