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Tuning the fluidity and protein corona of ultrasound-responsive liposomal nanovaccines to program T cell immunity in mice

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NATURE COMMUNICATIONS 2024年第1期15卷 8121页

作者： He, Jia Wang, Chaoyu Fang, Xiao Li, Junyao Shen, Xueying Zhang, Junxia Peng, Cheng Li, Hongjian Li, Sai Karp, Jeffrey M. Kuai, Rui Tsinghua Univ Sch Pharmaceut Sci Beijing Peoples R China Tsinghua Peking Ctr Life Sci Beijing Peoples R China Tsinghua Univ Sch Life Sci Beijing Peoples R China Frontier Res Ctr Biol Struct Beijing Peoples R China State Key Lab Membrane Biol Beijing Peoples R China Tsinghua Univ Sch Med Beijing Peoples R China Harvard Med Sch Brigham & Womens Hosp Dept Anesthesiol Perioperat & Pain Med Boston MA USA MIT Harvard MIT Program Hlth Sci & Technol Cambridge MA USA Harvard Univ Harvard Stem Cell Inst Cambridge MA USA Broad Inst MIT & Harvard Cambridge MA USA

Inducing high levels of antigen-specific CD8 alpha+ T cells in the tumor is beneficial for cancer immunotherapy, but achieving this in a safe and effective manner remains challenging. Here, we have developed a designer liposomal nanovaccine containing a sonosensitizer (LNVS) to efficiently program T cell immunity in mice. Following intravenous injection, LNVS accumulates in the spleen in a protein corona and fluidity-dependent manner, leading to greater frequencies of antigen-specific CD8 alpha+ T cells than soluble vaccines (the mixture of antigens and adjuvants). Meanwhile, some LNVS passively accumulates in the tumor, where it responds to ultrasound (US) to increase the levels of chemokines and adhesion molecules that are beneficial for recruiting CD8 alpha+ T cells to the tumor. LNVS + US induces higher levels of intratumoral antitumor T cells than traditional sonodynamic therapy, regresses established mouse MC38 tumors and orthotopic cervical cancer, and protects cured mice from relapse. Our platform sheds light on the importance of tuning the fluidity and protein corona of naovaccines to program T cell immunity in mice and may inspire new strategies for cancer immunotherapy. Delivery and fluidity of cancer nanoparticle vaccines alters efficiency and immune priming. Here the authors show a sonosensitive nanovaccine which depending on fluidity of the vaccine improves vaccine targeting and subsequent anti-tumour immune responses.

关键词： Nanoparticles Peptide delivery Tumour immunology Cytotoxic T cells

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ENVIRONMENTAL MONITORING program FOR THE MANUFACTURE OF cell AND GENE THERAPIES: START MAKING SENSE

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CYTOTHERAPY 2019年第5期21卷 S41-S41页

作者： Sdrolias, A. Velickovic, Z. Kan, F. Barry, N. Keir, M. Vincin, H. Chen, A. Favaloro, J. Chu, G. Macpherson, J. Rasko, J. Royal Prince Alfred Hosp Cell & Mol Therapies Camperdown NSW Australia Univ Sydney Fac Hlth & Med Sydney NSW Australia Centenary Inst Gene & Stem Cell Therapy Program Sydney NSW Australia

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Modular pooled discovery of synthetic knockin sequences to program durable cell therapies

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cell 2023年第19期186卷 4216-4234页

作者： Blaeschke, Franziska Chen, Yan Yi Apathy, Ryan Daniel, Bence Chen, Andy Y. Chen, Peixin Amy Sandor, Katalin Zhang, Wenxi Li, Zhongmei Mowery, Cody T. Yamamoto, Tori N. Nyberg, William A. To, Angela Yu, Ruby Bueno, Raymund Kim, Min Cheol Schmidt, Ralf Goodman, Daniel B. Feuchtinger, Tobias Eyquem, Justin Jimmie, Chun Carnevale, Julia Satpathy, Ansuman T. Shifrut, Eric Roth, Theodore L. Marson, Alexander Gladstone UCSF Inst Genom Immunol San Francisco CA 94158 USA Univ Calif San Francisco Dept Med San Francisco CA 94143 USA Stanford Univ Dept Pathol Stanford CA 94305 USA Stanford Univ Ctr Personal Dynam Regulomes Stanford CA 94305 USA Stanford Univ Dept Bioengn Stanford CA 94305 USA Univ Calif San Francisco Inst Human Genet IHG San Francisco CA 94143 USA Univ Calif San Francisco Diabet Ctr San Francisco CA 94143 USA Univ Calif San Francisco Parker Inst Canc Immunotherapy San Francisco CA 94129 USA Ludwig Maximilians Univ Munchen Univ Hosp Dr von Hauner Childrens Hosp Dept Pediat Hematol Oncol & Stem Cell Transplantat D-80337 Munich Germany German Canc Consortium DKTK Partner Site Munich D-80336 Munich Germany Natl Ctr Infect Res DZ D-81377 Munich Germany Univ Calif San Francisco Inst Computat Hlth Sci San Francisco CA 94143 USA Univ Calif San Francisco Dept Epidemiol & Biostat San Francisco CA 94143 USA Univ Calif San Francisco Dept Bioengn & Therapeut Sci San Francisco CA 94143 USA Univ Calif San Francisco Dept Microbiol & Immunol San Francisco CA 94143 USA Univ Calif Berkeley Innovat Genom Inst Berkeley CA 94720 USA Univ Calif San Francisco UCSF Helen Diller Family Comprehens Canc Ctr San Francisco CA 94158 USA Stanford Univ Program Immunol Stanford CA 94305 USA Med Univ Vienna Dept Lab Med Vienna Austria Tel Aviv Univ George S Wise Fac Life Sci Sch Neurobiol Biochem & Biophys IL-6997801 Tel Aviv Israel Tel Aviv Univ George S Wise Fac Life Sci Sch Neurobiol Biochem & Biophys IL-6997801 Tel Aviv Israel Tel Aviv Sourasky Med Ctr Dotan Ctr Adv Therapies IL-6423906 Tel Aviv Israel

Chronic stimulation can cause T cell dysfunction and limit the efficacy of cellular immunotherapies. Improved methods are required to compare large numbers of synthetic knockin (KI) sequences to reprogram cell functions. Here, we developed modular pooled KI screening (ModPoKI), an adaptable platform for modular construction of DNA KI libraries using barcoded multicistronic adaptors. We built two ModPoKI libraries of 100 transcription factors (TFs) and 129 natural and synthetic surface receptors (SRs). Over 30 ModPoKI screens across human TCR-and CAR-T cells in diverse conditions identified a transcription factor AP4 (TFAP4) construct that enhanced fitness of chronically stimulated CAR-T cells and anti-cancer function in vitro and in vivo. ModPoKI's modularity allowed us to generate an = 10,000-member library of TF combinations. Non-viral KI of a combined BATF-TFAP4 polycistronic construct enhanced fitness. Overexpressed BATF and TFAP4 co-occupy and regulate key gene targets to reprogram T cell function. ModPoKI facilitates the discovery of complex gene constructs to program cellular functions.

关键词： human T cells immunotherapy chimeric antigen receptor CRISPR pooled screens knockins transcription factor synthetic surface receptor chronic stimulation

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Establishing a robust chimeric antigen receptor T-cell therapy program in Australia: the Royal Prince Alfred Hospital experience

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CYTOTHERAPY 2022年第1期24卷 45-48页

作者： Velickovic, Zlatibor M. Rasko, John E. J. Royal Prince Alfred Hosp Dept Cell & Mol Therapies Sydney NSW Australia Centenary Inst Gene & Stem Cell Therapy Program Sydney NSW Australia Univ Sydney Fac Med & Hlth Sydney NSW Australia

Chimeric antigen receptor (CAR) T-cell therapy is a novel approved cancer treatment that has shown remarkable efficacy in the treatment of patients with relapsed leukemia and lymphoma. Implementation of CAR T-cell therapy in a hospital setting requires careful and detailed planning because of the complexities in delivering this specialist service. A multi-disciplinary approach with dedicated funding is required to meet clinical, scientific, logistic and regulatory requirements. Tisagenlecleucel was the first approved CAR T-cell therapy in Australia. The treatment has been made available to Australian patients in specialist public hospitals through federal and state funding. Royal Prince Alfred Hospital (RPAH) is one of Australia's oldest tertiary referral public health care institutions and was approved for the provision of CAR T-cell therapy service in 2019. A multi-disciplinary clinical program has been established for the collection and cryopreservation of donor cells shipped for manufacturing as well as for the receipt, storage and administration of CAR T-cell therapy and patient management. The program encompasses a Therapeutic Goods Administration -accredited apheresis unit and a state-of-the-art facility for cell processing, cryopreservation and storage. The program's clinical expertise extends to hematology, oncology, intensive care, pharmacy, neurology and radiology services with direct experience in managing patients receiving CAR T-cell therapies. The introduction of CAR T-cell therapies at RPAH was a complex undertaking facilitated by the existing infrastructure and clinical expertise. Crown Copyright (c) 2021. Published by Elsevier Inc. on behalf of International Society for cell & Gene Therapy. All rights reserved.

关键词： Australia CAR T-cell immunotherapy Royal Prince Alfred Hospital Sydney

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One stem cell program to rule them all?

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FEBS JOURNAL 2021年第11期288卷 3394-3406页

作者： Wiggans, Mallory Pearson, Bret J. Hosp Sick Children Program Dev & Stem Cell Biol Toronto ON M5G 0A4 Canada Univ Toronto Dept Mol Genet Toronto ON Canada Ontario Inst Canc Res Toronto ON Canada

Many species of animals have stem cells that they maintain throughout their lives, which suggests that stem cells are an ancestral feature of all animals. From this, we take the viewpoint that cells with the biological properties of 'stemness'-self-renewal and multipotency-may share ancestral genetic circuitry. However, in practice is it very difficult to identify and compare stemness gene signatures across diverse animals and large evolutionary distances? First, it is critical to experimentally demonstrate self-renewal and potency. Second, genomic methods must be used to determine specific gene expression in stem cell types compared with non-stem cell types to determine stem cell gene enrichment. Third, gene homology must be mapped between diverse animals across large evolutionary distances. Finally, conserved genes that fulfill these criteria must be tested for role in stem cell function. It is our viewpoint that by comparing stem cell-specific gene signatures across evolution, ancestral programs of stemness can be uncovered, and ultimately, the dysregulation of stemness programs drives the state of cancer stem cells.

关键词： cancer stem cells evolution planarians stem cells

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Construction of a digital twin of chronic graft vs. host disease patients with standard of care

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BONE MARROW TRANSPLANTATION 2024年第9期59卷 1280-1285页

作者： Li, Gen Chen, Yi-Bin Peachey, Jonathan Phesi East Lyme CT 06333 USA Massachusetts Gen Transplant Ctr Hematopoiet Cell Transplant & Cell Therapy Program Bone Marrow Transplant Program Boston MA USA

There is an unmet medical need for new clinical trials to evaluate novel therapies in chronic graft-versus-host disease (cGvHD). Disease rarity, ethical issues regarding placebo arms, time, and cost impede clinical trial conduct. Digital twin (DT) technology enables virtual clinical trial arm construction using historical data, circumventing these obstacles. We evaluated the feasibility of constructing a DT trial arm using a large database of real-world clinical trial data and performed an efficacy assessment of a standard-of-care (SOC) drug to examine agreement with literature data. We constructed a flGvHD DT cohort (cGvHD patients at first-line treatment) (2042 patients;32 cohorts) using the Trial Accelerator (TM) Digital Twin platform and derived an SOC arm from this cohort (flGvHD DT SOC cohort) (438 patients;eight cohorts);we analyzed the efficacy of SOC (prednisone) (overall response rate (ORR)) at six months. Our analysis results are in agreement with literature: flGvHD DT: disease onset time: 7.58 months post-allogeneic hematopoietic cell transplantation;most used graft source: peripheral blood stem cells;flGvHD DT SOC: ORR at six months for prednisone: 52.7%. It is feasible to construct a DT cohort using existing clinical trial data;a DT SOC arm can potentially replace a control arm in clinical trials.

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Cerebrospinal fluid flow extends to peripheral nerves further unifying the nervous system

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SCIENCE ADVANCES 2024年第36期10卷 eadn3259页

作者： Ligocki, Alexander P. Vinson, Augustine V. Yachnis, Anthony T. Dunn Jr, William A. Smith, Douglas E. Scott, Elizabeth A. Alvarez-Castanon, Jimena V. Montalvo, Daniel E. Baez Frisone, Olivia G. Brown, Gary A. J. Pessa, Joel E. Scott, Edward W. Univ Florida Coll Med Dept Mol Genet & Microbiol Program Stem Cell Biol & Regenerat Med Gainesville FL 32611 USA Univ Florida Coll Med Dept Pathol Immunol & Lab Med Program Stem Cell Biol & Regenerat Med Gainesville FL 32611 USA Univ Florida Coll Med Dept Anat & Cell Biol Program Stem Cell Biol & Regenerat Med Gainesville FL 32610 USA

Cerebrospinal fluid (CSF) is responsible for maintaining brain homeostasis through nutrient delivery and waste removal for the central nervous system (CNS). Here, we demonstrate extensive CSF flow throughout the peripheral nervous system (PNS) by tracing distribution of multimodal 1.9-nanometer gold nanoparticles, roughly the size of CSF circulating proteins, infused within the lateral cerebral ventricle (a primary site of CSF production). CSF-infused 1.9-nanometer gold transitions from CNS to PNS at root attachment/transition zones and distributes through the perineurium and endoneurium, with ultimate delivery to axoplasm of distal peripheral nerves. Larger 15-nanometer gold fails to transit from CNS to PNS and instead forms "dye-cuffs," as predicted by current dogma of CSF restriction within CNS, identifying size limitations in central to peripheral flow. Intravenous 1.9-nanometer gold is unable to cross the blood-brain/nerve barrier. Our findings suggest that CSF plays a consistent role in maintaining homeostasis throughout the nervous system with implications for CNS and PNS therapy and neural drug delivery.

关键词： Cerebrospinal fluid

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Implementation of an Education-Focused PhD program in Anatomy and cell Biology at Indiana University: Lessons Learned and Future Challenges

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ANATOMICAL SCIENCES EDUCATION 2015年第3期8卷 258-265页

作者： Brokaw, James J. O'Loughlin, Valerie D. Indiana Univ Sch Med Dept Anat & Cell Biol Indianapolis IN 46202 USA Indiana Univ Sch Med Med Sci Program Bloomington IN USA

In 2008, the Indiana University School of Medicine, in collaboration with the School of Education, admitted its first student to a newly approved PhD program in Anatomy and cell Biology focusing on educational research rather than biomedical research. The goal of the program is twofold: (1) to provide students with extensive training in all of the anatomical disciplines coupled with sufficient teaching experience to assume major educational responsibilities upon graduation and (2) to train students to conduct rigorous medical education research and other scholarly work necessary for promotion and tenure. The 90 credit hour curriculum consists of biomedical courses taught within the School of Medicine and education courses taught within the School of Education, including courses in health sciences pedagogy, curriculum development, learning theory, quantitative, and qualitative research methods, statistics, and electives. To date, 16 students have entered the program, seven have passed their qualifying examinations, and five have earned their PhD degrees. Four students have received national recognition for their educational research and four graduates have obtained faculty appointments. Going forward, we must adapt the program's biomedical course requirements to incorporate the new integrated curriculum of the medical school, and we must secure additional funding to support more students. Overcoming these challenges will enable us to continue producing a small but stable supply of doctoral-level anatomy educators for a growing academic market. Anat Sci Educ 8: 258-265. (c) 2014 American Association of Anatomists.

关键词： educational research anatomy education graduate education PhD curriculum scholarship of teaching and learning

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Proteomic Insight Into Alzheimer's Disease Pathogenesis Pathways

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PROTEOMICS 2025年第0期 e202400298页

作者： Ryu, Taekyung Kim, Kyungdo Asiimwe, Nicholas Na, Chan Hyun Johns Hopkins Univ Sch Med Inst Cell Engn Neuroregenerat Program Baltimore MD 21218 USA Johns Hopkins Univ Inst Cell Engn Sch Med Stem Cell Program Baltimore MD 21218 USA Johns Hopkins Univ Sch Med Dept Neurol Baltimore 21218 MD USA

Alzheimer's disease (AD) is a leading cause of dementia, but the pathogenesis mechanism is still elusive. Advances in proteomics have uncovered key molecular mechanisms underlying AD, revealing a complex network of dysregulated pathways, including amyloid metabolism, tau pathology, apolipoprotein E (APOE), protein degradation, neuroinflammation, RNA splicing, metabolic dysregulation, and cognitive resilience. This review examines recent proteomic findings from AD brain tissues and biological fluids, highlighting potential biomarkers and therapeutic targets. By examining the proteomic landscape of them, we aim to deepen our understanding of the disease and support developing precision medicine strategies for more effective interventions.

关键词： Alzheimer's disease biological pathway biomarkers mass spectrometry proteomics

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Overexpression of α-Klotho isoforms promotes distinct Effects on BDNF-Induced Alterations in Dendritic Morphology

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MOLECULAR NEUROBIOLOGY 2024年第11期61卷 9155-9170页

作者： Cararo-Lopes, Marina Minto Sadovnik, Ratchell Fu, Allen Suresh, Shradha Gandu, Srinivasa Firestein, Bonnie L. Rutgers State Univ Dept Cell Biol & Neurosci Piscataway NJ 08854 USA Rutgers State Univ Cell & Dev Biol Grad Program Piscataway NJ USA Rutgers State Univ Neurosci Grad Program Piscataway NJ USA

alpha-Klotho (alpha-Kl) is a modulator of aging, neuroprotection, and cognition. Transcription of the Klotho gene produces two splice variants-a membrane protein (mKl), which can be cleaved and released into the extracellular milieu, and a truncated secreted form (sKl). Despite mounting evidence supporting a role for alpha-Kl in brain function, the specific roles of alpha-Kl isoforms in neuronal development remain elusive. Here, we examined alpha-Kl protein levels in rat brain and observed region-specific expression in the adult that differs between isoforms. In the developing hippocampus, levels of isoforms decrease after the third postnatal week, marking the end of the critical period for development. We overexpressed alpha-Kl isoforms in primary cultures of rat cortical neurons and evaluated effects on brain-derived neurotrophic factor (BDNF) signaling. Overexpression of either isoform attenuated BDNF-mediated signaling and reduced intracellular Ca2+ levels, with mKl promoting a greater effect. mKl or sKl overexpression in hippocampal neurons resulted in a partially overlapping reduction in secondary dendrite branching. Moreover, mKl overexpression increased primary dendrite number. BDNF treatment of neurons overexpressing sKl resulted in a dendrite branching phenotype similar to control neurons. In neurons overexpressing mKl, BDNF treatment restored branching of secondary and higher order dendrites close, but not distal, to the soma. Taken together, the data presented support the idea that sKl and mKl play distinct roles in neuronal development, and specifically, in dendrite morphogenesis.

关键词： alpha-Klotho BDNF Dendrite branching TrkB signaling Calcium Neuronal development

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