tbuckley/cabot-search huggingface dataset:
Triptolide and its pro-drug Minnelide target high-risk MYC amplified medulloblastoma in preclinical models
Authors: Jezabel Rodriguez-Blanco, April D. Salvador, Robert K. Suter, Marzena Swiderska-Syn, Isabel Palomo-Caturla, Valentin Kliebe, Pritika Shahani, Kendell Peterson, Maria Turos-Cabal, Megan E. Vieira, Daniel T. Wynn, Ashley J. Howell, Fan Yang, Yuguang Ban, Heather J. McCrea, Frederique Zindy, Etienne Danis, Rajeev Vibhakar, Anna Jermakowicz, Vanesa Martin, Christopher C. Coss, Brent T. Harris, Aguirre de Cubas, X. Steven Chen, Thibaut Barnoud, Martine F. Roussel, Nagi G. Ayad, David J. Robbins
Journal: Journal of Clinical Investigation (2024)

Most children with medulloblastoma (MB) achieve remission, but some face very aggressive metastatic tumors. Their dismal outcome highlights the critical need to advance therapeutic approaches that benefit such high-risk patients. Minnelide, a clinically relevant analog of the natural product triptolide, has oncostatic activity in both preclinical and early clinical settings. Despite its efficacy and tolerable toxicity, this compound has not been evaluated in MB. Utilizing a bioinformatic dataset that integrates cellular drug response data with gene expression, we predicted that Group 3 (G3) MB, which has a poor five-year survival, would be sensitive to triptolide/Minnelide. We subsequently showed that both triptolide and Minnelide attenuate the viability of G3 MB cells ex vivo. Transcriptomic analyses identified MYC signaling, a pathologically relevant driver of G3 MB, as a downstream target of this class of drugs. We validated this MYC dependency in G3 MB cells and showed that triptolide exerts its efficacy by reducing both MYC transcription and MYC protein stability. Importantly, Minnelide acted on MYC to reduce tumor growth and leptomeningeal spread, which resulted in improved survival of G3 MB animal models. Moreover, Minnelide improved the efficacy of adjuvant chemotherapy, further highlighting its potential for the treatment of MYC-driven G3 MB patients.
Beneficial islet inflammation in health depends on pericytic TLR/MyD88 signaling
Authors: Anat Schonblum, Dunia Ali Naser, Shai Ovadia, Mohammed Egbaria, Shani Puyesky, Alona Epshtein, Tomer Wald, Sophia Mercado-Medrez, Ruth Ashery-Padan, Limor Landsman
Journal: Journal of Clinical Investigation (2024)

While inflammation is beneficial for insulin secretion during homeostasis, its transformation adversely affects β-cells and contributes to diabetes. However, the regulation of islet inflammation for maintaining glucose homeostasis remains largely unknown. Here, we identified pericytes as pivotal regulators of islet immune and β-cell function in health. Islets and pancreatic pericytes express various cytokines in healthy humans and mice. To interfere with the pericytic inflammatory response, we selectively inhibited the TLR/MyD88 pathway in these cells in transgenic mice. The loss of MyD88 impaired pericytic cytokine production. Furthermore, MyD88-deficient mice exhibited skewed islet inflammation with fewer cells, an impaired macrophage phenotype, and reduced IL-1β production. This aberrant pericyte-orchestrated islet inflammation was associated with β-cell dedifferentiation and impaired glucose response. Additionally, we found that Cxcl1, a pericytic MyD88-dependent cytokine, promoted immune IL-1β production. Treatments with either Cxcl1 or IL-1β restored the mature β-cell phenotype and glucose response in transgenic mice, suggesting a potential mechanism through which pericytes and immune cells regulate glucose homeostasis. Our study revealed pericyte-orchestrated islet inflammation as a crucial element in glucose regulation, implicating this process as a potential therapeutic target for diabetes.
The IFITM5 mutation in osteogenesis imperfecta type V is associated with an ERK/SOX9-dependent osteoprogenitor differentiation defect
Authors: Ronit Marom, I-Wen Song, Emily C. Busse, Megan E. Washington, Ava S. Berrier, Vittoria C. Rossi, Laura Ortinau, Youngjae Jeong, Ming-Ming Jiang, Brian C. Dawson, Mary Adeyeye, Carolina Leynes, Caressa D. Lietman, Bridget M. Stroup, Dominyka Batkovskyte, Mahim Jain, Yuqing Chen, Racel Cela, Alexis Castellon, Alyssa A. Tran, Isabel Lorenzo, D. Nicole Meyers, Shixia Huang, Alicia Turner, Vinitha Shenava, Maegen Wallace, Eric Orwoll, Dongsu Park, Catherine G. Ambrose, Sandesh C.S. Nagamani, Jason D. Heaney, Brendan H. Lee
Journal: Journal of Clinical Investigation (2024)

Osteogenesis imperfecta (OI) type V is the second most common form of OI, distinguished by hyperplastic callus formation and calcification of the interosseous membranes in addition to bone fragility. It is caused by a recurrent, dominant pathogenic variant (c.-14C>T) in IFITM5. Here, we generated a conditional Rosa26 knock-in mouse model to study the mechanistic consequences of the recurrent mutation. Expression of the mutant Ifitm5 in osteo-chondroprogenitor or chondrogenic cells resulted in low bone mass and growth retardation. Mutant limbs showed impaired endochondral ossification, cartilage overgrowth, and abnormal growth plate architecture. The cartilage phenotype correlates with the pathology reported in OI type V patients. Surprisingly, expression of mutant Ifitm5 in mature osteoblasts caused no obvious skeletal abnormalities. In contrast, earlier expression in osteo-chondroprogenitors was associated with increase in the skeletal progenitor population within the periosteum. Lineage tracing showed that chondrogenic cells expressing the mutant Ifitm5 showed decreased differentiation into osteoblastic cells in diaphyseal bone. Moreover, mutant IFITM5 disrupts early skeletal homeostasis in part by activating ERK signaling and downstream SOX9 protein, and inhibition of these pathways partially rescued the phenotype in mutant animals. These data identify the contribution of a signaling defect altering osteo-chondroprogenitor differentiation as a driver in the pathogenesis of OI type V.
WNK1 Interaction with KEAP1 Promotes NRF2 Stabilization to Enhance the Oxidative Stress Response in Hepatocellular Carcinoma
Authors: Li Li, Dacheng Xie, Shijun Yu, Muyuan Ma, Kailing Fan, Jingde Chen, Mengxi Xiu, Keping Xie, Yandong Li, Yong Gao
Journal: Cancer Research (2024)

Abstract Cellular oxidative stress plays a key role in the development and progression of hepatocellular carcinoma (HCC). A better understanding of the processes that regulate reactive oxygen species (ROS) homeostasis could uncover improved strategies for treating HCC. Herein, we identified protein kinase with-no-lysine kinase 1 (WNK1) as an antioxidative factor and therapeutic target in HCC. In human HCC, WNK1 expression was increased and correlated with poor patient prognosis. WNK1 knockdown significantly inhibited cell proliferation and xenograft tumor growth. Mechanistically, WNK1 competed with nuclear factor erythroid 2–related factor 2 (NRF2) for binding with the partial Kelch domain of Kelch-like ECH-associated protein 1 (KEAP1), reducing NRF2 ubiquitination and promoting NRF2 accumulation and nuclear translocation to increase antioxidant response. WNK1 silencing increased H2O2-induced apoptosis and inhibited cell growth by elevating ROS levels, which could be rescued by treatment with the antioxidant N-acetylcysteine and NRF2 activator tert-butylhydroquinone. Liver-specific WNK1 knockout mouse models of HCC substantiated that WNK1 promoted HCC development by regulating ROS levels. WNK463, an inhibitor of the WNK kinase family, suppressed HCC progression and altered the redox status. These findings suggest that WNK1 plays a critical role in HCC development and progression and that the WNK1-oxidative stress axis may be a promising therapeutic target for HCC. Significance: Inhibiting WNK1 induces NRF2 degradation and reduces the oxidative stress response to suppress hepatocellular carcinoma growth, indicating that targeting the WNK1–KEAP1–NRF2 axis is a potential strategy to treat liver cancer.
Oncogenic Calreticulin Induces Immune Escape by Stimulating TGF-β Expression and Regulatory T Cell Expansion in the Bone Marrow Microenvironment
Authors: Dominik Schmidt, Cornelia Endres, Rouven Hoefflin, Geoffroy Andrieux, Melissa Zwick, Nikolaos Karantzelis, Hans F. Staehle, Janaki Manoja Vinnakota, Sandra Duquesne, Miriam Mozaffari Jovein, Dietmar Pfeifer, Heiko Becker, Bruce R. Blazar, Alexander Zähringer, Justus Duyster, Tilman Brummer, Melanie Boerries, Julian Baumeister, Khalid Shoumariyeh, Juan Li, Anthony R. Green, Florian H. Heidel, Itay Tirosh, Heike L. Pahl, Nils Leimkühler, Natalie Köhler, Marcelo A.S. de Toledo, Steffen Koschmieder, Robert Zeiser
Journal: Cancer Research (2024)

Abstract Increasing evidence supports the interplay between oncogenic mutations and immune escape mechanisms. Strategies to counteract the immune escape mediated by oncogenic signaling could provide improved therapeutic options for patients with various malignancies. As mutant calreticulin (CALR) is a common driver of myeloproliferative neoplasms (MPN), we analyzed the impact of oncogenic CALRdel52 on the bone marrow (BM) microenvironment in MPN. Single-cell RNA-sequencing revealed that CALRdel52 led to the expansion of TGF-β1-producing erythroid progenitor cells and promoted the expansion of FoxP3+ regulatory T cells (Treg) in a murine MPN model. Treatment with an anti-TGF-β antibody improved mouse survival and increased the glycolytic activity in CD4+ and CD8+ T cells in vivo, while T cell depletion abrogated the protective effects conferred by neutralizing TGF-β. TGF-β1 reduced perforin and TNF-α production by T cells in vitro. TGF-β1 production by CALRdel52 cells was dependent on JAK1/2, PI3K, and ERK activity, which activated the transcription factor Sp1 to induce TGF-β1 expression. In four independent patient cohorts, TGF-β1 expression was increased in the BM of MPN patients compared to healthy individuals, and the BM of MPN patients contained a higher frequency of Treg compared to healthy individuals. Together, this study identified an ERK/Sp1/TGF-β1 axis in CALRdel52 MPNs as a mechanism of immunosuppression that can be targeted to elicit T-cell-mediated cytotoxicity.
Healthy aging meta-analyses and scoping review of risk factors across Latin America reveal large heterogeneity and weak predictive models
Authors: Agustin Ibanez, Marcelo Maito, Felipe Botero-Rodríguez, Sol Fittipaldi, Carlos Coronel, Joaquin Migeot, Andrea Lacroix, Brian Lawlor, Claudia Duran-Aniotz, Sandra Baez, Hernando Santamaria-Garcia
Journal: Nature Aging (2024)

Abstract Models of healthy aging are typically based on the United States and Europe and may not apply to diverse and heterogeneous populations. In this study, our objectives were to conduct a meta-analysis to assess risk factors of cognition and functional ability across aging populations in Latin America and a scoping review focusing on methodological procedures. Our study design included randomized controlled trials and cohort, case–control and cross-sectional studies using multiple databases, including MEDLINE, the Virtual Health Library and Web of Science. From an initial pool of 455 studies, our meta-analysis included 38 final studies (28 assessing cognition and 10 assessing functional ability, n = 146,000 participants). Our results revealed significant but heterogeneous effects for cognition (odds ratio (OR) = 1.20, P = 0.03, confidence interval (CI) = (1.0127, 1.42); heterogeneity: I 2 = 92.1%, CI = (89.8%, 94%)) and functional ability (OR = 1.20, P = 0.01, CI = (1.04, 1.39); I 2 = 93.1%, CI = (89.3%, 95.5%)). Specific risk factors had limited effects, especially on functional ability, with moderate impacts for demographics and mental health and marginal effects for health status and social determinants of health. Methodological issues, such as outliers, inter-country differences and publication bias, influenced the results. Overall, we highlight the specific profile of risk factors associated with healthy aging in Latin America. The heterogeneity in results and methodological approaches in studying healthy aging call for greater harmonization and further regional research to understand healthy aging in Latin America.
Response by Jeong et al to Letter Regarding Article, “Early Left Ventricular Unloading or Conventional Approach After Venoarterial Extracorporeal Membrane Oxygenation: The EARLY-UNLOAD Randomized Clinical Trial”
Authors: In-Seok Jeong, Min Chul Kim, Yongwhan Lim, Youngkeun Ahn
Journal: Circulation (2024)
Advanced Cardiac Patches for the Treatment of Myocardial Infarction
Authors: Tailuo Liu, Ying Hao, Zixuan Zhang, Hao Zhou, Shiqin Peng, Dingyi Zhang, Ka Li, Yuwen Chen, Mao Chen
Journal: Circulation (2024)

Myocardial infarction is a cardiovascular disease characterized by a high incidence rate and mortality. It leads to various cardiac pathophysiological changes, including ischemia/reperfusion injury, inflammation, fibrosis, and ventricular remodeling, which ultimately result in heart failure and pose a significant threat to global health. Although clinical reperfusion therapies and conventional pharmacological interventions improve emergency survival rates and short-term prognoses, they are still limited in providing long-lasting improvements in cardiac function or reversing pathological progression. Recently, cardiac patches have gained considerable attention as a promising therapy for myocardial infarction. These patches consist of scaffolds or loaded therapeutic agents that provide mechanical reinforcement, synchronous electrical conduction, and localized delivery within the infarct zone to promote cardiac restoration. This review elucidates the pathophysiological progression from myocardial infarction to heart failure, highlighting therapeutic targets and various cardiac patches. The review considers the primary scaffold materials, including synthetic, natural, and conductive materials, and the prevalent fabrication techniques and optimal properties of the patch, as well as advanced delivery strategies. Last, the current limitations and prospects of cardiac patch research are considered, with the goal of shedding light on innovative products poised for clinical application.
Single-stranded DNA Gap Accumulation is a Functional Biomarker for USP1 Inhibitor Sensitivity
Authors: Alexandre André B A. da Costa, Ozge Somuncu, Ramya Ravindranathan, Sirisha Mukkavalli, David B. Martignetti, Huy Nguyen, Yuqing Jiao, Benjamin P. Lamarre, Golbahar Sadatrezaei, Lisa Moreau, Joyce Liu, Divya R. Iyer, Jean-Bernard Lazaro, Geoffrey I. Shapiro, Kalindi Parmar, Alan D. D'Andrea
Journal: Cancer Research (2024)

Abstract Recent studies suggest that PARP inhibitors and POLQ inhibitors confer synthetic lethality in BRCA1-deficient tumors by accumulation of single-stranded DNA (ssDNA) gaps at replication forks. Loss of USP1, a deubiquitinating enzyme, is also synthetic lethal with BRCA1 deficiency, and USP1 inhibitors are now undergoing clinical development for these cancers. Here, we show that USP1 inhibitors also promote the accumulation of ssDNA gaps during replication in BRCA1-deficient cells, and this phenotype correlates with the drug sensitivity. USP1 inhibition increased monoubiquitinated PCNA at replication forks, mediated by the ubiquitin ligase RAD18, and knockdown of RAD18 caused USP1 inhibitor resistance and suppression of ssDNA gaps. USP1 inhibition overcame PARP inhibitor resistance in a BRCA1-mutated xenograft model and induced ssDNA gaps. Furthermore, USP1 inhibition was synergistic with PARP and POLQ inhibition in BRCA1-mutant cells, with enhanced ssDNA gap accumulation. Finally, in patient-derived ovarian tumor organoids, sensitivity to USP1 inhibition alone or in combination correlated with the accumulation of ssDNA gaps. Assessment of ssDNA gaps in ovarian tumor organoids therefore represents a rapid approach for predicting response to USP1 inhibition in ongoing clinical trials.
Effects of Dapagliflozin on Body Composition and Its Relation to Hemodynamics in Heart Failure With Preserved Ejection Fraction
Authors: Jwan A. Naser, Atsushi Tada, Tomonari Harada, Yogesh N.V. Reddy, Rickey E. Carter, Jeffrey M. Testani, Michael D. Jensen, Barry A. Borlaug
Journal: Circulation (2024)
Targeted immunotherapy and nanomedicine for rhabdomyosarcoma: The way of the future
Authors: Victoria Judith Morel, Jochen Rössler, Michele Bernasconi
Journal: Medicinal Research Reviews (2024)

Abstract Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. Histology separates two main subtypes: embryonal RMS (eRMS; 60%–70%) and alveolar RMS (aRMS; 20%–30%). The aggressive aRMS carry one of two characteristic chromosomal translocations that result in the expression of a PAX3::FOXO1 or PAX7::FOXO1 fusion transcription factor; therefore, aRMS are now classified as fusion‐positive (FP) RMS. Embryonal RMS have a better prognosis and are clinically indistinguishable from fusion‐negative (FN) RMS. Next to histology and molecular characteristics, RMS risk groupings are now available defining low risk tumors with excellent outcomes and advanced stage disease with poor prognosis, with an overall survival of about only 20% despite intensified multimodal treatment. Therefore, development of novel effective targeted strategies to increase survival and to decrease long‐term side effects is urgently needed. Recently, immunotherapies and nanomedicine have been emerging for potent and effective tumor treatments with minimal side effects, raising hopes for effective and safe cures for RMS patients. This review aims to describe the most relevant preclinical and clinical studies in immunotherapy and targeted nanomedicine performed so far in RMS and to provide an insight in future developments.
Transient Differentiation-State Plasticity Occurs During Acute Lymphoblastic Leukemia Initiation
Authors: Vera M. Poort, Rico Hagelaar, Markus J. van Roosmalen, Laurianne Trabut, Jessica G. C. A. M. Buijs-Gladdines, Bram van Wijk, Jules Meijerink, Ruben van Boxtel
Journal: Cancer Research (2024)

Abstract Leukemia is characterized by oncogenic lesions that result in a block of differentiation, whereas phenotypic plasticity is retained. A better understanding of how these two phenomena arise during leukemogenesis in humans could help inform diagnosis and treatment strategies. Here, we leveraged the well-defined differentiation states during T-cell development to pinpoint the initiation of T-cell acute lymphoblastic leukemia (T-ALL), an aggressive form of childhood leukemia, and study the emergence of phenotypic plasticity. Single-cell whole genome sequencing of leukemic blasts was combined with multiparameter flow cytometry to couple cell identity and clonal lineages. Irrespective of genetic events, leukemia-initiating cells altered their phenotypes by differentiation and dedifferentiation. The construction of the phylogenies of individual leukemias using somatic mutations revealed that phenotypic diversity is reflected by the clonal structure of cancer. The analysis also indicated that the acquired phenotypes are heritable and stable. Together, these results demonstrate a transient period of plasticity during leukemia initiation, where phenotypic switches seem unidirectional. Significance: A method merging multicolor flow cytometry with single-cell whole genome sequencing to couple cell identity with clonal lineages uncovers differentiation-state plasticity in leukemia, reconciling blocked differentiation with phenotypic plasticity in cancer.
Responsive Multi‐Arm PEG‐Modified COF Nanocomposites: Dynamic Photothermal, pH/ROS Dual‐Responsive, Targeted Carriers for Rheumatoid Arthritis Treatment
Authors: Saisai Ge, Xinyue Wang, Xinru Zhao, Lingling Yuan, Xuewei Bao, Caidie Sun, Zehua Gong, Jun Guo, Siyu Yuan, Danyou Hu, Jing Yang, Bin Yuan, Guiyang Zhang
Journal: Advanced Healthcare Materials (2024)

Rheumatoid arthritis (RA) is a chronic immune disease characterized by the infiltration of immune cells and the proliferation of fibroblast-like synoviocytes (FLS) at the joint site, leading to inflammation and joint destruction. However, the available treatment options targeting both inflammatory and proliferative FLS are limited. Herein, this work presents three covalent organic frameworks (COFs) photothermal composite systems modified with multi-armed polyethylene glycols (PEG) for the treatment of RA. These systems exhibit a dual response under low pH and high reactive oxygen species (ROS) conditions at the site of inflammation, with a specific focus on delivering the protein drug ribonuclease A (RNase A). Notably, molecular docking studies reveal the interaction between RNase A and NF-κB p65 protein, and Western blotting confirm its inhibitory effect on NF-κB activity. In vitro and in vivo experiments verify the significant reduction in joint swelling and deformities in adjuvant-induced arthritis (AIA) rats after treatment with RNase A delivered by multi-armed PEG-modified COF ligands, restoring joint morphology to normal. These findings underscore the promising therapeutic potential of COFs for the treatment of RA, highlighting their unique capabilities in addressing both inflammatory and proliferative aspects of the disease and expanding the scope of biomedical applications for COFs.
Author Correction: Direct and selective pharmacological disruption of the YAP–TEAD interface by IAG933 inhibits Hippo-dependent and RAS–MAPK-altered cancers
Authors: Emilie A. Chapeau, Laurent Sansregret, Giorgio G. Galli, Patrick Chène, Markus Wartmann, Thanos P. Mourikis, Patricia Jaaks, Sabrina Baltschukat, Ines A. M. Barbosa, Daniel Bauer, Saskia M. Brachmann, Clara Delaunay, Claire Estadieu, Jason E. Faris, Pascal Furet, Stefanie Harlfinger, Andreas Hueber, Eloísa Jiménez Núñez, David P. Kodack, Emeline Mandon, Typhaine Martin, Yannick Mesrouze, Vincent Romanet, Clemens Scheufler, Holger Sellner, Christelle Stamm, Dario Sterker, Luca Tordella, Francesco Hofmann, Nicolas Soldermann, Tobias Schmelzle
Journal: Nature Cancer (2024)
In vitro and in vivo evaluation of biohybrid tissue-engineered vascular grafts with transformative 1H/19F MRI traceable scaffolds
Authors: Elena Rama, Saurav Ranjan Mohapatra, Yukiharu Sugimura, Tomoyuki Suzuki, Stefan Siebert, Roman Barmin, Juliane Hermann, Jasmin Baier, Anne Rix, Teresa Lemainque, Susanne Koletnik, Asmaa Said Elshafei, Roger Molto Pallares, Seyed Mohammadali Dadfar, René H. Tolba, Volkmar Schulz, Joachim Jankowski, Christian Apel, Payam Akhyari, Stefan Jockenhoevel, Fabian Kiessling
Journal: Biomaterials (2024)

Biohybrid tissue-engineered vascular grafts (TEVGs) promise long-term durability due to their ability to adapt to hosts' needs. However, the latter calls for sensitive non-invasive imaging approaches to longitudinally monitor their functionality, integrity, and positioning. Here, we present an imaging approach comprising the labeling of non-degradable and degradable TEVGs' components for their in vitro and in vivo monitoring by hybrid
SARS-CoV-2 humoral immunity in people living with HIV-1
Authors: Boitumelo M. Motsoeneng, Jinal N. Bhiman, Simone I. Richardson, Penny L. Moore
Journal: Trends in Immunology (2024)

The effect of COVID-19 on the high number of immunocompromised people living with HIV-1 (PLWH), particularly in Africa, remains a critical concern. Here, we identify key areas that still require further investigation, by examining COVID-19 vaccine effectiveness, and understanding antibody responses in SARS-CoV-2 infection and vaccination in comparison with people without HIV-1 (PWOH). We also assess the potential impact of pre-existing immunity against endemic human coronaviruses on SARS-CoV-2 responses in these individuals. Lastly, we discuss the consequences of persistent infection in PLWH (or other immunocompromised individuals), including prolonged shedding, increased viral diversity within the host, and the implications on SARS-CoV-2 evolution in Africa.