tbuckley/cabot-search huggingface dataset:
Rapid modulation of gut microbiota composition by hypothalamic circuits in mice
Authors: Míriam Toledo, Sara Martínez-Martínez, Matthias Van Hul, Berta Laudo, Elena Eyre, Rudy Pelicaen, Anthony Puel, Jordi Altirriba, Alicia G Gómez-Valadés, Julica Inderhees, Isabel Moreno-Indias, Macarena Pozo, Iñigo Chivite, Maria Milà-Guasch, Roberta Haddad-Tóvolli, Arnaud Obri, Júlia Fos-Domènech, Iasim Tahiri, Sergio R Llana, Sara Ramírez, Erika Monelli, Markus Schwaninger, Patrice D Cani, Rubén Nogueiras, Marc Claret
Journal: Nature Metabolism (2025)

In recent years, the gut microbiota and derived metabolites have emerged as relevant players in modulating several brain functions, including energy balance control1-3. This form of distant communication mirrors that of metabolic hormones (for example, leptin, ghrelin), which convey information about the organism's energy status by exerting effects on diverse brain regions, including the master homeostatic centre, the hypothalamus4. However, whether the hypothalamus is also able to influence gut microbiota composition remains enigmatic. Here we present a study designed to unravel this challenging question. To this aim, we used chemogenetics5 (to selectively activate or inhibit hypothalamic pro-opiomelanocortin or agouti-related peptide neurons) or centrally administered leptin or ghrelin to male mice. Subsequently, we conducted microbiota composition analysis throughout the gut using 16S rRNA gene sequencing. Our results showed that these brain interventions significantly changed the gut microbiota in an anatomical and short-term (2-4 h) fashion. Transcriptomic analysis indicated that these changes were associated with the reconfiguration of neuronal and synaptic pathways in the duodenum concomitant with increased sympathetic tone. Interestingly, diet-induced obesity attenuated the brain-mediated changes triggered by leptin in gut microbiota communities and sympathetic activation. Our findings reveal a previously unanticipated brain-gut axis that acutely attunes microbiota composition on fast timescales, with potential implications for meal-to-meal adjustments and systemic energy balance control.
Multimetric MRI Captures Early Response and Acquired Resistance of Pancreatic Cancer to KRAS Inhibitor Therapy
Authors: Mamta Gupta, Hoon Choi, Samantha B. Kemp, Emma E. Furth, Stephen Pickup, Cynthia Clendenin, Margo Orlen, Mark Rosen, Fang Liu, Quy Cao, Ben Z. Stanger, Rong Zhou
Journal: Clinical Cancer Research (2025)

Abstract Purpose: In pancreatic ductal adenocarcinoma (PDAC), KRAS mutations drive both cancer cell growth and formation of a dense stroma. Small molecule KRAS inhibitors (KRASi) represent a promising new treatment hence clinical tools that can assess early response, detect resistance and/or predict prolonged survival are desirable to understand clinical biology of KRASi. We hypothesized that diffusion-weighted MRI (DWI) can detect cell death while dynamic contrast enhanced MRI (DCE) and magnetization transfer ratio (MTR) imaging are sensitive to tumor microenvironment changes, and these metrics shed insights into tumor size change induced by KRASi treatment. Experimental Design: Multiple preclinical PDAC models including a genetically engineered mouse model (KPC) received MRTX1133, a KRASi specific for KRASG12D mutation. Quantitative imaging markers were corroborated with immunohistochemistry (IHC) analyses. Results: Significant increase of tumor apparent diffusion coefficient (a DWI metric) was detected as early as 48h and persisted to Day7 after initiation of KRASi treatment and was strongly correlated with cell death and reduced cellularity, resulting in greatly prolonged median survival in treated mice. Capillary perfusion/permeability (a DCE metric) exhibited an inverse relationship with microvascular density. Distinct responses of KRASG12C versus KRASG12D tumors to MRTX1133 were captured by the MRI metrics corroborated with IHC. When tumors developed resistance to MRTX1133, the imaging marker values exhibited a reversal from those of responding tumors. Conclusions: Multiparametric MRI provides early biological insights of cancer and stromal response to KRASi treatment and sets the stage for testing the utility of these clinically ready MRI methods in patients receiving KRASi therapy.
Antisense oligonucleotide treatment in a preterm infant with early-onset SCN2A developmental and epileptic encephalopathy
Authors: Matias Wagner, Géza Berecki, Walid Fazeli, Claudia Nussbaum, Andreas W Flemmer, Silvana Frizzo, Farina Heer, Florian Heinen, Robert Horton, Henry Jacotin, William Motel, Brian Spar, Christoph Klein, Corinna Siegel, Christoph Hübener, Sophia Stöcklein, Marco Paolini, Martin Staudt, Moritz Tacke, Markus Wolff, Steven Petrou, Marcio Souza, Ingo Borggraefe
Journal: Nature Medicine (2025)
The retrotransposon-derived capsid genes PNMA1 and PNMA4 maintain reproductive capacity
Authors: Thomas W P Wood, William S Henriques, Harrison B Cullen, Mayra Romero, Cecilia S Blengini, Shreya Sarathy, Julia Sorkin, Hilina Bekele, Chen Jin, Seungsoo Kim, Xifan Wang, Raphaelle Laureau, Alexei Chemiakine, Rishad C Khondker, José V V Isola, Michael B Stout, Vincenzo A Gennarino, Binyam Mogessie, Devanshi Jain, Karen Schindler, Yousin Suh, Blake Wiedenheft, Luke E Berchowitz
Journal: Nature Aging (2025)
Endothelial dysfunction drives atherosclerotic plaque macrophage-dependent abdominal aortic aneurysm formation
Authors: Danya Thayaparan, Takuo Emoto, Aniqa B Khan, Rickvinder Besla, Homaira Hamidzada, Mahmoud El-Maklizi, Tharini Sivasubramaniyam, Shabana Vohra, Ash Hagerman, Sara Nejat, Charlotte E Needham-Robbins, Tao Wang, Moritz Lindquist, Steven R Botts, Stephanie A Schroer, Masayuki Taniguchi, Taishi Inoue, Katsuhiro Yamanaka, Haotian Cui, Edouard Al-Chami, Hangjun Zhang, Marwan G Althagafi, Aja Michalski, Joshua J C McGrath, Steven P Cass, David Luong, Yuya Suzuki, Angela Li, Amina Abow, Rachel Heo, Shaun Pacheco, Emily Chen, Felix Chiu, John Byrne, Tomoyuki Furuyashiki, Mansoor Husain, Peter Libby, Kenji Okada, Kathryn L Howe, Scott P Heximer, Tomoya Yamashita, Bo Wang, Barry B Rubin, Myron I Cybulsky, Joy Roy, Jesse W Williams, Sarah Q Crome, Slava Epelman, Ken-Ichi Hirata, Martin R Stampfli, Clinton S Robbins
Journal: Nature Immunology (2025)
Level-Ground and Stair Adaptation for Hip Exoskeletons Based on Continuous Locomotion Mode Perception
Authors: Zhaoyang Wang, Dongfang Xu, Shunyi Zhao, Zehuan Yu, Yan Huang, Lecheng Ruan, Zhihao Zhou, Qining Wang
Journal: Cyborg and Bionic Systems (2025)

Hip exoskeleton can provide assistance to users to augment movements in different scenarios. The assistive control for hip exoskeleton involves the interactions among exoskeleton, user, and environment, which depends on the environment perception (to predict locomotion) to design control strategy combined with gait mode and so on. Current exoskeleton control still needs to be improved in adaptation to continuous locomotion mode and different users. To address this problem, we have employed a learning-free (i.e., non-data-driven) environment perception method to improve hip exoskeleton adaptive control toward continuous locomotion mode. The adaptive control experiments were conducted on level ground and stairs on 7 subjects. The prediction accuracy for steady locomotion mode was more than 95% for each subject (ranged from 95.7% to 99.7%). The prediction accuracy for each locomotion mode transition ranged from 87.5% to 100%, and the transition timing could be detected before the end of transition period. Compared with learning-based (data-driven) approaches, our method achieves better performances in adaptive control for hip exoskeleton and shows some generalization for subjects.
Outcomes in immunocompromised patients with acute hypoxemic respiratory failure treated by high-flow nasal oxygen
Authors: Elie Azoulay, Mélanie Métais, Virginie Lemiale, Djamel Mokart, Anne-Sophie Moreau, Emmanuel Canet, Achille Kouatchet, Laurent Argaud, Peter Pickkers, Philippe R Bauer, Andry van de Louw, Ignacio Martin-Loeches, Sangeeta Mehta, Christophe Girault, Florent Wallet, Frédéric Pène, Alexandre Demoule, Alexis Maillard
Journal: Intensive Care Medicine (2025)
Transforming Malignant Tumors into Vulnerable Phenotypes via Nanoscale Coordination Polymer Mediated Cell Senescence and Photodynamic Therapy
Authors: Wenyao Zhen, Xiaomin Jiang, En Li, Tomas Germanas, Morten J Lee, Taokun Luo, Xin Ma, Chaoyu Wang, Yimei Chen, Ralph R Weichselbaum, Wenbin Lin
Journal: Biomaterials (2025)
B cell-derived exosomal miR-483-5p and its potential role in promoting kidney function loss in IgA nephropathy
Authors: Izabella Za Pawluczyk, Jasraj S Bhachu, Jeremy R Brown, Michael Lacey, Chidimma Mbadugha, Kees Straatman, David Wimbury, Haresh Selvaskandan, Jonathan Barratt
Journal: Kidney International (2025)
SynMSE: A Multimodal Similarity Evaluator for Complex Distribution Discrepancy in Unsupervised Deformable Multimodal Medical Image Registration
Authors: Jingke Zhu, Boyun Zheng, Bing Xiong, Yuxin Zhang, Ming Cui, Deyu Sun, Jing Cai, Yaoqin Xie, Wenjian Qin
Journal: Medical Image Analysis (2025)
Efficacy of Benznidazole Delivery During Chagas Disease Nanotherapy is Dependent on the Nanocarrier Morphology
Authors: Debora B Scariot, Austeja Staneviciute, Rayanne R B Machado, Simseok A Yuk, Yu-Gang Liu, Swagat Sharma, Sultan Almunif, El Hadji Arona Mbaye, Celso Vataru Nakamura, David M Engman, Evan A Scott
Journal: Biomaterials (2025)
Abstract 1423: Locus-specific proteomics to define transcriptional regulation of GUCY2C hormone expression in colorectal cancer
Authors: Adi Caspi, Ariana A. Entezari, Jasmine R. Alvarez, Jeffrey A. Rappaport, Adam E. Snook, Scott A. Waldman
Journal: Cancer Research (2025)

Abstract The GUCY2C intestinal receptor regulates fluid secretion and epithelial transformation through its hormone ligand guanylin (GUCA2A). GUCY2C supports intestinal homeostasis and has been characterized as a tumor suppressor in colorectal cancer. In early tumorigenesis, GUCY2C signaling is silenced through transcriptional repression of guanylin. Guanylin repression is mediated by Wnt/β-catenin/TCF4, a critical signaling pathway aberrantly activated in ∼90% of colorectal cancers. Specifically, Wnt signaling regulates expression at a recently characterized 2, 683-base pair locus control region (LCR) upstream of the GUCA2A gene. This regulation is conferred indirectly, and TCF4, the transcription factor effector of the Wnt cascade, does not interact with the LCR. However, many downstream TCF4 targets are transcription factors canonically implicated in tumorigenesis. Therefore, our goal is to identify factors specifically interacting with the LCR and regulating guanylin expression. Colorectal cancer cell lines expressing inducible Wnt-silencing constructs were used to toggle the expression of guanylin. Using these models, we sought to interrogate Wnt regulation at the LCR by employing C-BERST (dCas9-APEX2 biotinylation at genomic elements by restricted spatial tagging), an unbiased proteomics-based approach to profile locus-specific protein interactions. This system relies on peroxidase-mediated biotinylation of proteins by a dCas9-APEX2 fusion protein, driven to a locus of interest by a targeting gRNA. Following localized biotinylation, proteins are enriched by streptavidin pulldown and identified by mass spectrometry analysis. Assessing proteins in the presence and absence of Wnt signaling can reveal Wnt-regulated factors controlling target gene expression. By ChIP-qPCR, we have captured the GUCA2A gene locus using targeted gRNAs. Further, dCas9-APEX2 binding does not interfere with the expression of guanylin or its Wnt regulation. Finally, streptavidin-based pulldowns reveal protein interactions at the promoter that can be further characterized by mass spectrometry to elucidate the Wnt regulatory machinery at the GUCA2A locus. Identifying the mechanism of Wnt-mediated guanylin silencing, and the transcription factors controlling that regulation, will provide novel insights to inform therapeutic targeting to reconstitute the GUCY2C signaling axis to prevent colorectal cancer. Citation Format: Adi Caspi, Ariana A. Entezari, Jasmine R. Alvarez, Jeffrey A. Rappaport, Adam E. Snook, Scott A. Waldman. Locus-specific proteomics to define transcriptional regulation of GUCY2C hormone expression in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1423.
Abstract 1235: Complex in vitro tumor models screen NK therapy and reveal mode of action
Authors: Bin Xue, Christopher Harrod, Long Le, Julia Schueler, Kolin C. Hribar
Journal: Cancer Research (2025)

Abstract NK cell therapy is an emerging and increasingly promising modality for various cancers. Whereas T cell-based adoptive cell therapy (e.g. tumor infiltrating lymphocytes or TILs, and CAR-T) is mainly limited to patient’s autologous cells due to concerns around allogeneic responses with MHC (major histocompatibility complex) mismatch, NK therapies do not suffer from this due to their low risk of introducing GvHD (Graft-versus-host disease), enabling the development of NK therapies using either patient-sourced NK cells or allogeneic, healthy donor-sourced cells. NK therapies have demonstrated early success in some hematologic cancer, however, the inadequate infiltration and persistence in the tumor microenvironment (TME) limits their application in solid tumors. Therefore, the ability to model solid tumors in vitro to screen efficacy and study mode of action would be highly beneficial to gaining early and actionable insights for clinical translation. Here, we developed several patient-derived xenograft (PDX) 3D in vitro non-small cell lung or colorectal cancer models using a proprietary hydrogel platform. The platform resembles the TME to enable consistent growth of tumor cells, fibroblast elongation, and immune cell interactions. An activated NK cell population (“NK therapy”), featuring CD56bright CD16+ (∼50%) and CD56bright CD16- (∼50%) phenotypes by flow cytometry, was highly potent in the 3D models. These NK therapy cells demonstrated a significant increase in tumor infiltration and tumor cytotoxicity compared to the non-activated NK (“NK control”) counterparts from the same donor. Interestingly, key cytokines like IFNg were downregulated in the NK therapy as compared to the NK control. These data demonstrate a robust and comprehensive in vitro analysis for NK therapy, offering a new preclinical tool for validating their effectiveness and mode of action. Citation Format: Bin Xue, Christopher Harrod, Long Le, Julia Schueler, Kolin C. Hribar. Complex in vitro tumor models screen NK therapy and reveal mode of action [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1235.
Abstract 1654: Discovery of the first-in-class DOT1L PROTAC degrader
Authors: Hyerin Yim, Zhongli Xu, Husnu Kaniskan, Jian Jin
Journal: Cancer Research (2025)

The histone methyltransferase, DOT1L is often dysregulated in MLL-rearranged (MLL-r) leukemia, which leads to hyperactivation of MLL target genes and poor prognosis. This dysregulation is particularly common in infants, who are highly vulnerable to treatment-related toxicity. However, current treatment options remain limited, with intensive chemotherapy as the standard approach. Given these circumstances, targeting DOT1L with PROteolysis TArgeting Chimeras (PROTACs) could represent a promising alternative therapeutic strategy. Here, we report the discovery of the first-in-class DOT1L PROTAC degrader, MS2133, which induces DOT1L degradation in a dose- and time-dependent manner via the ubiquitin-proteasome system, without affecting DOT1L mRNA expression. MS2133 shows selectivity for DOT1L over other methyltransferases and effectively inhibits the growth of MLL-r leukemia cells while having no toxic effect on normal cells. Overall, MS2133 is a valuable chemical biology tool for studying DOT1L functions and offers promise as a therapeutic option for MLL-r leukemia treatment. Citation Format: Hyerin Yim, Zhongli Xu, Husnu Kaniskan, Jian Jin. Discovery of the first-in-class DOT1L PROTAC degrader [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1654.
Abstract 1441: Elevated HOXC gene expression in castration-resistant prostate cancer
Authors: Isaacson B. Adelani, Akira Kurozumi, Tobiloba Owojuyigbe, Sanchit Sanyal, Su Mi Choi, Srinivasan Yegnasubramanian, Shawn E. Lupold
Journal: Cancer Research (2025)

Abstract Background: Androgen deprivation therapy or Androgen receptor-targeted therapies are used to treat metastatic Prostate Cancer (PCa). However, nearly all cases eventually progress to castration-resistant prostate cancer (CRPC). The molecular pathways associated with CRPC development and progression remain incompletely defined. This study aims to identify new drivers and delineate the underlying mechanisms in CRPC. Methods: Three isogenic castration-sensitive and castration-resistant prostate cancer cell lines were analyzed by miRNA and RNA sequencing. Gene transcripts associated with castration resistance were further characterized by RT-PCR and bioinformatic analyses. Gene knockout and knockdown in CRPC cell lines were carried out using the CRISPR/Cas9 technology and RNA interference (RNAi) technique. In addition, the HOXC gene cluster was overexpressed in castration-sensitive prostate cancer cell lines using predesigned synthetic sgRNAs and the CRISPR activation (CRISPRa) system. Cell growth and survival were assessed using the IncuCyte®-SX5 live cell analysis system. Results: Differential gene expression analysis identified significantly elevated miR-196a expression in CRPC cell lines. Visualization of RNA sequencing read density peaks in IGV revealed pri-miR-196a-2 as the source of elevated miR-196a expression in CRPC cells. MIR196A2 is located within the HOXC gene cluster. Transcriptional analyses demonstrate that miR-196a-2 is an intronic miRNA co-transcribed within HOXC gene transcripts. Multiple HOXC gene transcripts were more active in CRPC cell lines. Bioinformatic analyses demonstrated significantly higher HOXC gene expression in a subset of metastatic and CRPC tumors. The elevated expression was further validated in clinical samples by RT-qPCR. HOXC8 gene over-expression using plasmid gene expression vectors and CRISPRa enhanced prostate cancer cell proliferation, and HOXC8 gene knockout attenuated CRPC cell proliferation. Conclusions: HOXC gene cluster is activated in in a subset of metastatic and castration-resistant prostate cancer with HOXC8 playing a crucial role in regulating cell proliferation. Citation Format: Isaacson B. Adelani, Akira Kurozumi, Tobiloba Owojuyigbe, Sanchit Sanyal, Su Mi Choi, Srinivasan Yegnasubramanian, Shawn E. Lupold. Elevated HOXC gene expression in castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1441.
Abstract 1852: Uncovering regulatory mechanisms and therapeutic targets in EV-mediated nanoparticle transfer: A proteomics and high-throughput screening approach
Authors: Xian Wu, Hong-Bo Pang
Journal: Cancer Research (2025)

Abstract Extracellular vesicles (EVs) are naturally occurring vesicles that facilitate the transfer of biomolecules between cells, playing a vital role in cellular communication and regulation. Recently, EVs have been discovered participating active transport of nanomaterials between cells, suggesting a novel method to enhance the delivery of nanoparticles. A 3D intercellular exchange assay has been developed by our group to monitor and quantify EV-mediated transfer of silver nanoparticles (AgNPs) across different cell types. Furthermore, distinct EV subpopulations, those containing AgNPs (AgNP-containing) and those without (AgNP-free), were isolated from AgNP-exposed cells using density gradient ultracentrifugation. In this study, we leverage proteomics and high-throughput screening (HTS) to reveal the regulatory mechanisms of EV-mediated intercellular communication and identify compounds that regulate this process. Using mass spectrometry and advanced bioinformatics, unique protein signatures associated with each EV type were identified, uncovering biomarkers that indicate origin and functional relevance in EV-mediated transport process. To investigate potential regulators of EV-mediated intercellular exchange, we combined HTS with our 3D intercellular exchange assay to identify compounds that modulate EV-mediated transfer of nanomaterials. Integrating HTS with quantitative proteomics enabled us to identify key compounds that specifically impact the formation and secretion of AgNP-free and AgNP-containing EV subpopulations. These findings not only provide new insights into the regulatory mechanisms controlling nanomaterial-sorting and EV genesis but also highlight potential therapeutic targets for modulating EV-mediated intercellular exchange, which may further improve nanomedicine delivery. This work underscores the utility of combining proteomics and HTS for the discovery of small molecules capable of regulating EV-mediated transfer, with implications for therapeutic development and biomarker discovery. Citation Format: Xian Wu, Hong-Bo Pang. Uncovering regulatory mechanisms and therapeutic targets in EV-mediated nanoparticle transfer: A proteomics and high-throughput screening approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1852.