tbuckley/cabot-search huggingface dataset:
Preclinical evaluation of antigen-sensitive B7-H3-targeting nanobody-based CAR-T cells in glioblastoma cautions for on-target, off-tumor toxicity
Authors: Fien Meeus, Cyprine Neba Funeh, Robin Maximilian Awad, Katty Zeven, Dorien Autaers, Ann De Becker, Ivan Van Riet, Cleo Goyvaerts, Sandra Tuyaerts, Bart Neyns, Nick Devoogdt, Yannick De Vlaeminck, Karine Breckpot
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Glioblastoma is the most common lethal primary brain tumor, urging evaluation of new treatment options. Chimeric antigen receptor (CAR)-T cells targeting B7 homolog 3 (B7-H3) are promising because of the overexpression of B7-H3 on glioblastoma cells but not on healthy brain tissue. Nanobody-based (nano)CARs are gaining increasing attention as promising alternatives to classical single-chain variable fragment-based (scFv)CARs, because of their single-domain nature and low immunogenicity. Still, B7-H3 nanoCAR-T cells have not been extensively studied in glioblastoma. Methods B7-H3 nanoCAR- and scFvCAR-T cells were developed and evaluated in human glioblastoma models. NanoCAR-T cells targeting an irrelevant antigen served as control. T cell activation, cytokine secretion and killing capacity were evaluated in vitro using ELISA, live cell imaging and flow cytometry. Antigen-specific killing was assessed by generating B7-H3 knock-out cells using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9-genome editing. The tumor tracing capacity of the B7-H3 nanobody was first evaluated in vivo using nuclear imaging. Then, the therapeutic potential of the nanoCAR-T cells was evaluated in a xenograft glioblastoma model. Results We showed that B7-H3 nanoCAR-T cells were most efficient in lysing B7-H3 pos glioblastoma cells in vitro. Lack of glioblastoma killing by control nanoCAR-T cells and lack of B7-H3 neg glioblastoma killing by B7-H3 nanoCAR-T cells showed antigen-specificity. We showed in vivo tumor targeting capacity of the B7-H3 nanobody—used for the nanoCAR design—in nuclear imaging experiments. Evaluation of the nanoCAR-T cells in vivo showed tumor control in mice treated with B7-H3 nanoCAR-T cells in contrast to progressive disease in mice treated with control nanoCAR-T cells. However, we observed limiting toxicity in mice treated with B7-H3 nanoCAR-T cells and showed that the B7-H3 nanoCAR-T cells are activated even by low levels of mouse B7-H3 expression. Conclusions B7-H3 nanoCAR-T cells showed promise for glioblastoma therapy following in vitro characterization, but limiting in vivo toxicity was observed. Off-tumor recognition of healthy mouse tissue by the cross-reactive B7-H3 nanoCAR-T cells was identified as a potential cause for this toxicity, warranting caution when using highly sensitive nanoCAR-T cells, recognizing the low-level expression of B7-H3 on healthy tissue.
Successful treatment of in-transit metastatic melanoma with combination intralesional T-VEC and topical imiquimod immunotherapy
Authors: Marisa Lenga, Esther Choi, Jeffrey Sosman, Sunandana Chandra, Danielle Lam, Kirsten Johnson, Lauren Schiemann, Jennifer Choi
Journal: Journal for ImmunoTherapy of Cancer (2024)

In-transit metastases of malignant melanoma pose a significant clinical challenge, particularly in patients with contraindications to systemic therapies. While surgical excision and systemic immunotherapies remain standard treatments, localized therapies such as intralesional talimogene laherparepvec (T-VEC) and topical imiquimod, which stimulate tumor-specific T-cell responses, have garnered increasing attention for their potential efficacy and tolerability. Although the individual efficacy of these therapies is well-documented, their combined use and their synergistic effects have not been well-documented. This case series reports on five patients with in-transit melanoma metastases treated with T-VEC and imiquimod at Northwestern Memorial Hospital from November 2018 to May 2023. Patients received a median of 13 (range 8–20) T-VEC injections over a median of 6 months (range 5–9), of which 4 of those months were with concurrent T-VEC and imiquimod cream. Four of the five patients achieved complete response (CR) by the end of the treatment course. One patient developed systemic progression during therapy, leading to early cessation of treatment. All patients with CR elected to continue topical imiquimod applications as maintenance following T-VEC for a median of 6 months (range 2–14 months). Only one of the four patients who achieved CR developed metastatic nodal disease 10 months after the last T-VEC injection. The three other patients are free of cutaneous and systemic disease 2–57 months after their last injection. All patients tolerated treatment well with zero patients discontinuing treatment due to side effects. These findings suggest that the combination of intralesional T-VEC and topical imiquimod can be an effective and safe treatment of in-transit metastases of malignant melanoma.
Examining the replicability of online experiments selected by a decision market
Authors: Felix Holzmeister, Magnus Johannesson, Colin F. Camerer, Yiling Chen, Teck-Hua Ho, Suzanne Hoogeveen, Juergen Huber, Noriko Imai, Taisuke Imai, Lawrence Jin, Michael Kirchler, Alexander Ly, Benjamin Mandl, Dylan Manfredi, Gideon Nave, Brian A. Nosek, Thomas Pfeiffer, Alexandra Sarafoglou, Rene Schwaiger, Eric-Jan Wagenmakers, Viking Waldén, Anna Dreber
Journal: Nature Human Behaviour (2024)

Abstract Here we test the feasibility of using decision markets to select studies for replication and provide evidence about the replicability of online experiments. Social scientists ( n = 162) traded on the outcome of close replications of 41 systematically selected MTurk social science experiments published in PNAS 2015–2018, knowing that the 12 studies with the lowest and the 12 with the highest final market prices would be selected for replication, along with 2 randomly selected studies. The replication rate, based on the statistical significance indicator, was 83% for the top-12 and 33% for the bottom-12 group. Overall, 54% of the studies were successfully replicated, with replication effect size estimates averaging 45% of the original effect size estimates. The replication rate varied between 54% and 62% for alternative replication indicators. The observed replicability of MTurk experiments is comparable to that of previous systematic replication projects involving laboratory experiments.
Author Correction: NK cell receptor NKG2D sets activation threshold for the NCR1 receptor early in NK cell development
Authors: Vedrana Jelenčić, Marko Šestan, Inga Kavazović, Maja Lenartić, Sonja Marinović, Tim D. Holmes, Michaela Prchal-Murphy, Berislav Lisnić, Veronika Sexl, Yenan T. Bryceson, Felix M. Wensveen, Bojan Polić
Journal: Nature Immunology (2024)
Endogenous Glucagon‐Like Peptide‐1 Receptor and Glucose‐Dependent Insulinotropic Polypeptide Receptor Signaling Inhibits Aeroallergen‐Induced Innate Airway Inflammation
Authors: Shinji Toki, Masako Abney, Jian Zhang, Mark Rusznak, Christian M. Warren, Dawn C. Newcomb, Katherine N. Cahill, Daniel J. Drucker, Kevin D. Niswender, Ray Stokes Peebles
Journal: Allergy (2024)

Anti-inflammatory effects of incretin signaling through the glucagon-like peptide-1 receptor (GLP-1R) and the glucose-dependent insulinotropic polypeptide receptor (GIPR) in mice have been reported. Therefore, we hypothesized that signaling through the endogenous GLP-1R and the GIPR individually decreases allergic airway inflammation and that the combination of GLP-1R and GIPR signaling together additively inhibits allergen-induced lung and airway inflammation.
Stress-experienced monocytes/macrophages lose anti-inflammatory function via β2-adrenergic receptor in skin allergic inflammation
Authors: Hitoshi Urakami, Soichiro Yoshikawa, Kei Nagao, Kensuke Miyake, Yuki Fujita, Ayaka Komura, Miho Nakashima, Ryusuke Umene, Shuhei Sano, Zheyu Hu, Emi Nishii, Atsushi Fujimura, Takeshi Y Hiyama, Keiji Naruse, Hajime Karasuyama, Tsuyoshi Inoue, Mitsutoshi Tominaga, Kenji Takamori, Shin Morizane, Sachiko Miyake
Journal: Journal of Allergy and Clinical Immunology (2024)
Dorsal root ganglion toxicity after AAV intra-CSF delivery of a RNAi expression construct into nonhuman primates and mice
Authors: Zachary C E Hawley, Ingrid D Pardo, Shaolong Cao, Maria I Zavodszky, Fergal Casey, Kyle Ferber, Yi Luo, Sam Hana, Shukkwan K Chen, Jessica Doherty, Raquel Costa, Patrick Cullen, Yuqing Liu, Thomas M Carlile, Twinkle Chowdhury, Benjamin Doyle, Pete Clarner, Kevin Mangaudis, Edward Guilmette, Shawn Bourque, David Koske, Murali V P Nadella, Patrick Trapa, Michael L Hawes, Denitza Raitcheva, Shih-Ching Lo
Journal: Molecular Therapy (2024)
Long-read RNA sequencing: a transformative technology for exploring transcriptome complexity in human diseases
Authors: Isabelle Heifetz Ament, Nicole DeBruyne, Feng Wang, Lan Lin
Journal: Molecular Therapy (2024)

Long-read RNA sequencing (RNA-seq) is emerging as a powerful and versatile technology for studying human transcriptomes. By enabling the end-to-end sequencing of full-length transcripts, long-read RNA-seq opens up avenues for investigating various RNA species and features that cannot be reliably interrogated by standard short-read RNA-seq methods. In this review, we present an overview of long-read RNA-seq, delineating its strengths over short-read RNA-seq, as well as summarizing recent advances in experimental and computational approaches to boost the power of long-read-based transcriptomics. We describe a wide range of applications of long-read RNA-seq, and highlight its expanding role as a foundational technology for exploring transcriptome variations in human diseases.
Orthogonal transcriptional modulation and gene editing using multiple CRISPR/Cas systems
Authors: Amalie Dyrelund Broksø, Louise Bendixen, Simon Fammé, Kasper Mikkelsen, Trine Ilsø Jensen, Rasmus O Bak
Journal: Molecular Therapy (2024)

CRISPR/Cas-based transcriptional activation (CRISPRa) and interference (CRISPRi) enable transient programmable gene regulation by recruitment or fusion of transcriptional regulators to nuclease-deficient Cas (dCas). Here we expand on the emerging area of transcriptional engineering and RNA delivery by benchmarking combinations of RNA-delivered dCas and transcriptional modulators. We utilize dCas9 from Staphylococcus aureus and Streptococcus pyogenes for orthogonal transcriptional modulation to upregulate one set of genes while downregulating another. We also establish trimodal genetic engineering by combining orthogonal transcriptional regulation with gene knockout by Cas12a (Acidaminococcus; AsCas12a) ribonucleoprotein (RNP) delivery. To simplify trimodal engineering, we explore optimal parameters for implementing truncated sgRNAs to make use of SpCas9 for knockout and CRISPRa. We find the Cas9 protein:sgRNA ratio to be crucial for avoiding sgRNA cross-complexation and for balancing knockout and activation efficiencies. We demonstrate high efficiencies of trimodal genetic engineering in primary human T cells while preserving basic T cell health and functionality. This study highlights the versatility and potential of complex genetic engineering using multiple CRISPR/Cas systems in a simple, one-step process yielding transient transcriptome modulation and permanent DNA changes. We believe such elaborate engineering can be implemented in regenerative medicine and therapies to facilitate more sophisticated treatments.
Targeting PD-1+ T cells with small-format immunocytokines enhances IL-12 antitumor activity
Authors: Noelia Silva-Pilipich, Uxue Beloki, Patricia Apaolaza, Ana Igea, Laura Salaberry, Laura Prats-Mari, Eric Rovira, Marina Ondiviela, Marta Gorraiz, Juan José Lasarte, Lucía Vanrell, Cristian Smerdou
Journal: Molecular Therapy (2024)
Structure and Sequence Engineering Approaches to Improve In Vivo Expression of Nucleic Acid-Delivered Antibodies
Authors: Michaela Helble, Jacqueline Chu, Kaitlyn Flowers, Abigail R Trachtman, Alana Huynh, Amber Kim, Nicholas Shupin, Casey E Hojecki, Ebony N Gary, Shahlo Solieva, Elizabeth M Parzych, David B Weiner, Daniel W Kulp, Ami Patel
Journal: Molecular Therapy (2024)
Longitudinal imaging of therapeutic enzyme expression after gene therapy for Fabry disease using Positron Emission Tomography and the radiotracer [18F]AGAL
Authors: Charalambos Kaittanis, Tyler Teceno, Ashley Knight, Yoann Petibon, Phil Sandoval, Lawrence Cohen, Shin Hye Ahn, Anthony P Belanger, Louise M Clark, Quang-De Nguyen, Wanida Ruangsiriluk, Shreya Mukherji, Cristian C Constantinescu, Amy Llopis Amenta, Sarav Narayanan, Mugdha Deshpande, Rizwana Islam, Shipeng Yuan, Paul McQuade, Christopher T Winkelmann, Talakad G Lohith
Journal: Molecular Therapy (2024)
Next‐Gen Poly(ε‐Caprolactone) Scaffolds: Non‐Destructive In Vivo Monitoring and Accelerated Biodegradation
Authors: Kristyna Kolouchova, Quinten Thijssen, Ondrej Groborz, Lana Van Damme, Jana Humajova, Petr Matous, Astrid Quaak, Martin Dusa, Jan Kucka, Ludek Sefc, Martin Hruby, Sandra Van Vlierberghe
Journal: Advanced Healthcare Materials (2024)

Poly(ɛ-caprolactone) (PCL) is a biocompatible, biodegradable, and highly mechanically resilient FDA-approved material (for specific biomedical applications, e.g. as drug delivery devices, in sutures, or as an adhesion barrier), rendering it a promising candidate to serve bone tissue engineering. However, in vivo monitoring of PCL-based implants, as well as biodegradable implants in general, and their degradation profiles pose a significant challenge, hindering further development in the tissue engineering field and subsequent clinical adoption. To address this, photo-cross-linkable mechanically resilient PCL networks are developed and functionalized with a radiopaque monomer, 5-acrylamido-2,4,6-triiodoisophthalic acid (AATIPA), to enable non-destructive in vivo monitoring of PCL-based implants. The covalent incorporation of AATIPA into the crosslinked PCL networks does not significantly affect their crosslinking kinetics, mechanical properties, or thermal properties, but it increases their hydrolysis rate and radiopacity. Complex and porous 3D designs of radiopaque PCL networks can be effectively monitored in vivo. This work paves the way toward non-invasive monitoring of in vivo degradation profiles and early detection of potential implant malfunctions.
In Situ Sprayed Hydrogel Delivers Extracellular Vesicles Derived from Human Endometrial Organoids for Uterine Function Preservation and Fertility Restoration
Authors: Xunsi Qin, Kai‐Lun Hu, Qi Li, Yuze Sun, Tianliu Peng, Xiyao Liu, Jizhou Li, Wenhui Nan, Yang Yu, Xiangbing Qi, Rong Li
Journal: Advanced Healthcare Materials (2024)

Abstract Impaired endometrial function and reduced receptivity remain significant causes of female infertility. Here, a sprayable hydrogel combined with human endometrial organoid extracellular vesicles (HEO‐EVs) is developed to enhance uterine function preservation and fertility restoration. The peptide amphiphile hydrogel (labeled CPA) is engineered by conjugating a collagen‐binding peptide with glutathione to impart its biocompatible adhesive and antioxidant properties. The therapeutic EVs are isolated and purified from human endometrial organoids that have been stably passaged long‐term using a bioreactor‐culture system. The resulting HEO‐EVs‐loaded CPA (CPA@HEO‐EVs) rapid gelation, triggered by salt‐ion interactions, occurs when the fluid is sprayed onto the uterine lining. The ex vivo studies demonstrate that CPA@HEO‐EVs promote cell proliferation, scavenges free radicals, and increases tube formation in human umbilical vein endothelial cells. In vivo experiments further validate that in situ spraying with the CPA@HEO‐EVs can promote neovascularization, prevent localized endometrial fibrosis, and effectively enhance fertility in a mouse model of endometrial injury. These findings highlight the promising clinical application of in situ sprayed CPA@HEO‐EVs hydrogel for targeted endometrial therapy.
Hydrogel‐Forming Microneedles and Applications in Interstitial Fluid Diagnostic Devices
Authors: Angélica F. Aroche, Hannah E. Nissan, Michael A. Daniele
Journal: Advanced Healthcare Materials (2024)

Abstract Hydrogel‐forming microneedles are constructed from or coated with polymeric, hydrophilic materials that swell upon insertion into the skin. Designed to dissolve or disintegrate postinsertion, these microneedles can deliver drugs, vaccines, or other therapeutics. Recent advancements have broadened their application scope to include the collection, transport, and extraction of dermal interstitial fluid (ISF) for medical diagnostics. This review presents a brief introduction to the characteristics of dermal ISF, methods for extraction and sampling, and critical assessment of the state‐of‐the‐art in hydrogel‐forming microneedles for ISF diagnostics. Key factors are evaluated including material composition, swelling behavior, biocompatibility, and mechanical strength necessary for effective microneedle performance and ISF collection. The review also discusses successful examples of dermal ISF assays and microneedle sensor integrations, highlighting notable achievements, identifying research opportunities, and addressing challenges with potential solutions. Despite the predominance of synthetic hydrogels in reported hydrogel‐forming microneedle technologies due to their favorable swelling and gelation properties, there is a significant variety of biopolymers and composites reported in the literature. The field lacks consensus on the optimal material, composition, or fabrication methods, though emerging evidence suggests that processing and fabrication techniques are critical to the performance and utility of hydrogel‐forming microneedles for ISF diagnostics.
Natural Extracellular Matrix Scaffold‐Based Hydrogel Corneal Patch with Temperature and Light‐Responsiveness for Penetrating Keratoplasty and Sutureless Stromal Defect Repair
Authors: Long Zhao, Zhen Shi, Jingting Wang, Shengqian Dou, Xiuli Sun, Shang Yang, Hongwei Wang, Qingjun Zhou, Ting Wang, Weiyun Shi
Journal: Advanced Healthcare Materials (2024)

Abstract Corneal transplantation remains the gold standard for treating corneal blindness; however, it is hampered globally by donor shortages and the complexity of suture‐dependent procedures. Tissue‐engineered corneas have demonstrated potential as corneal equivalents. Nevertheless, the development of adhesive corneal patches and full‐thickness corneal substitutes remains challenging. In this study, a multifunctional hydrogel corneal patch (MHCP) is constructed by integrating a dual‐crosslinked hybrid hydrogel with temperature and light responsiveness with a natural extracellular matrix scaffold. When applied to the ocular surface, MHCP spontaneously releases adhesives at body temperature and forms a stable adhesion with the recipient cornea through photocuring. In addition to its inherent mechanical, optical, and ultrastructural characteristics, which are similar to those of the natural stroma, MHCP demonstrates excellent suture resistance, anti‐swelling, and anti‐degradation properties after curing. MHCP promotes the proliferation and migration of corneal epithelial cells in vitro and maintains the phenotype of corneal stromal cells. In vivo, MHCP maintains graft hydration and restores corneal structural integrity and transparency during penetrating keratoplasty of various sizes and sutureless lamellar keratoplasty. Collectively, given the advantages of native stroma‐like characteristics, operation‐facilitating multiple functions, and convenient preparation, MHCP is a promising corneal substitute for clinical applications.
The critical role of endoplasmic reticulum stress and the stimulator of interferon genes (STING) pathway in kidney fibrosis.
Authors: Magaiver Andrade-Silva, Poonam Dhillon, Andrea Sanchez-Navarro, Dhanunjay Mukhi, Hailong Hu, Lakshmi P Kolligundla, Andrea Bergeson, Amin Abedini, Jonathan Levinsohn, Bernhard Dumoulin, Niels O S Câmara, Jonathan J Miner, Katalin Susztak
Journal: Kidney International (2024)
Microbiota-derived small molecule genotoxins: host interactions and ecological impact in the gut ecosystem
Authors: Ellen L. Zechner, Sabine Kienesberger
Journal: Gut Microbes (2024)

The human intestinal tract is densely colonized by a microbial community that is subject to intense competition. Bacteria in this complex habitat seek to outcompete their neighbors for nutrients and eliminate competitors with antibacterial toxins. Antagonism can be mediated by diverse effectors including toxic proteins and small molecule inhibitors that are released extracellularly or delivered by specialized secretion systems to targeted cells. Two prototypical microbiota-derived enterotoxins, colibactin and tilimycin, and the newly discovered family of indolimines represent an expanding group of non-proteinaceous small molecules which specifically target DNA. In addition to cell killing, they generate mutations and genome instability in intoxicated microbes and host cells alike. They have been studied in detail because of their direct toxicity to human cells and important etiological roles in intestinal pathologies. Increasing evidence, however, reveals that these commensal genotoxins are also mediators of interbacterial antagonism, which impacts gut microbial ecology. In this review, we illustrate the functional versatility of commensal genotoxins in the gut ecosystem.
The role of allogeneic stem cell transplantation in acute myeloid leukemia with translocation t(8;16)(p11;p13)
Authors: Ann‐Kristin Schmälter, Myriam Labopin, Jurjen Versluis, Maria Pilar Gallego Hernanz, Matthias Eder, Peter von dem Borne, Gerard Socié, Patrice Chevallier, Edouard Forcade, Andreas Neubauer, Frédéric Baron, Ali Bazarbachi, Gesine Bug, Arnon Nagler, Christoph Schmid, Jordi Esteve, Mohamad Mohty, Fabio Ciceri
Journal: American Journal of Hematology (2024)

Abstract Acute myeloid leukemia (AML) with translocation t(8;16)(p11;p13) represents a rare entity that has been categorized as a disease‐defining recurring cytogenetic abnormality with adverse risk in the 2022 European LeukemiaNet classification. This rating was mainly based on a retrospective analysis comprising patients from several large clinical trials, which, however, included only 21 patients treated with allogeneic stem cell transplantation (alloSCT). Therefore, the European Society for Blood and Marrow Transplantation performed a registry study on a larger cohort to evaluate the role of alloSCT in t(8;16) AML. Sixty transplant recipients with t(8;16) AML were identified. Two‐year overall and leukemia‐free survival (OS/LFS) was 43/39%. Patients transplanted in first complete remission (CR1, n = 44) achieved a 2‐year OS/LFS of 48%/48%. Following alloSCT in CR1, the multivariable analysis identified a complex karyotype (CK) as a major risk factor for relapse (HR 4.17, p = .016), lower LFS (HR 3.38, p = .01), and lower OS (HR 3.08, p = .017). Two‐year OS/LFS of patients with CK was 19%/19%, in contrast to 67%/67% in patients with t(8;16) outside a CK. Other factors for inferior outcomes were older age and secondary AML. In summary, alloSCT could mitigate the adverse risk of patients with t(8;16) AML not harboring a CK, particularly when performed in CR1.