tbuckley/cabot-search huggingface dataset:
Action Programed Nanoantibiotics with pH‐Induced Collapse and Negative‐Charged‐Surface‐Induced Deformation Against Antibiotic‐Resistant Bacterial Peritonitis
Authors: Xiao Zhang, Penghui Liu, Ran Zhang, Wenhong Zheng, Di Qin, Yinghang Liu, Xin Wang, Tongyi Sun, Yuanyuan Gao, Li‐Li Li
Journal: Advanced Healthcare Materials (2024)

The incorporation of well-designed antibiotic nanocarriers, along with an antibiotic adjuvant effect, in combination with various antibiotics, offers an opportunity to combat drug-resistant strains. However, precise control over morphology and encapsulated payload release can significantly impact their antibacterial efficacy and synergistic effects when used alongside antibiotics. Here, this study focuses on developing lipopeptide-based nanoantibiotics, which demonstrate an antibiotic adjuvant effect by inducing pH-induced collapse and negative-charged-surface-induced deformation. This enhances the disruption of the bacterial outer membrane and facilitates drug penetration, effectively boosting the antimicrobial activity against drug-resistant strains. The modulation regulations of the lipopeptide nanocarriers with modular design are governed by the authors. The nanoantibiotics, made from lipopeptide and ciprofloxacin (Cip), have a drug loading efficiency of over 80%. The combination with Cip results in a significantly low fractional inhibitory concentration index of 0.375 and a remarkable reduction in the minimum inhibitory concentration of Cip against multidrug-resistant (MDR) Escherichia coli (clinical isolated strains) by up to 32-fold. The survival rate of MDR E. coli peritonitis treated with nanoantibiotics is significantly higher, reaching over 87%, compared to only 25% for Cip and no survival for the control group. Meanwhile, the nanoantibiotic shows no obvious toxicity to major organs.
Amivantamab plus lazertinib versus osimertinib in first-line EGFR-mutant advanced non-small-cell lung cancer with biomarkers of high-risk disease: a secondary analysis from MARIPOSA
Authors: E. Felip, B.C. Cho, V. Gutiérrez, A. Alip, B. Besse, S. Lu, A.I. Spira, N. Girard, R. Califano, S.M. Gadgeel, J.C.-H. Yang, S. Yamamoto, K. Azuma, Y.J. Kim, K.-H. Lee, P. Danchaivijitr, C.G. Ferreira, Y. Cheng, M.A.N. Sendur, G.-C. Chang, C.-C. Wang, K. Prabhash, Y. Shinno, D. Stroyakovskiy, L. Paz-Ares, J.R. Rodriguez-Cid, C. Martin, M.R.G. Campelo, H. Hayashi, D. Nguyen, P. Tomasini, M. Gottfried, C. Dooms, A. Passaro, M. Schuler, A.C.Z. Gelatti, S. Owen, K. Perdrizet, S.-H.I. Ou, J.C. Curtin, J. Zhang, M. Gormley, T. Sun, A. Panchal, M. Ennis, E. Fennema, M. Daksh, S. Sethi, J.M. Bauml, S.-H. Lee
Journal: Annals of Oncology (2024)

Amivantamab-lazertinib significantly prolonged progression-free survival (PFS) versus osimertinib in patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small-cell lung cancer [NSCLC; hazard ratio (HR) 0.70; P < 0.001], including those with a history of brain metastases (HR 0.69). Patients with TP53 co-mutations, detectable circulating tumor DNA (ctDNA), baseline liver metastases, and those without ctDNA clearance on treatment have poor prognoses. We evaluated outcomes in these high-risk subgroups.
Effect of 48 Months of Closed-Loop Insulin Delivery on Residual C-Peptide Secretion and Glycemic Control in Newly Diagnosed Youth With Type 1 Diabetes: A Randomized Trial
Authors: Julia Ware, Charlotte K. Boughton, Janet M. Allen, Malgorzata E. Wilinska, Sara Hartnell, Ajay Thankamony, Tabitha Randell, Atrayee Ghatak, Rachel E.J. Besser, Daniela Elleri, Nicola Trevelyan, Fiona M. Campbell, Judy Sibayan, Ryan Bailey, Peter Calhoun, Gareth Dunseath, Roman Hovorka, Tabitha Randell, Vreni Verhoeven, Roman Hovorka, Ajay Thankmonay, Carlo Acerini, David Dunger, Charlotte Boughton, Julia Ware, Martin Tauschmann, Rama Lakshman, Janet Allen, Malgorzata Wilinska, Sara Hartnell, Alina Cezar, Nicole Ashcroft, Mirela de Barros Tamarozzi, Meena Murthy, Atrayee Ghatak, Keith Thornborough, Jonathon Mimnagh, Joanne Shakeshaft, Karen Phelan, Rachel Besser, Rebecca Law, Clare Megson, Jane Haest, Alison West, Imogen Stamford, Daniela Elleri, Morag McDonald, Nicola Trevelyan, Helen Dewar, Rachel Brampton, Gabrielle Price, Gillian Crouch, Fiona Campbell, James Yong, Emily Metcalfe, Andrew Cameron, Julia Lawton, David Rankin, Judy Sibayan, Peter Calhoun, Ryan Bailey, Jessica Rusnak, Brian Bugielski, Gareth Dunseath, Stephen Luzio, Elisabeth Northam, John Todd, Stéphane Roze, Eleanor Scott, Tim Jones, Chris Patterson, Peter Adolfsson, John Gregory, Stephen Greene, Jo Blair, Alexia Passmore
Journal: Diabetes Care (2024)

We evaluated the effect of long-term intensive metabolic control with hybrid closed-loop (CL) on residual C-peptide secretion and glucose control compared with standard insulin therapy in youth with type 1 diabetes over 48 months.
Single Cell Analysis Reveals Novel Immune Perturbations in Fibrotic Hypersensitivity Pneumonitis
Authors: Amy Y Zhao, Avraham Unterman, Nebal S. Abu Hussein, Prapti Sharma, Fadi Nekola, Jasper Flint, Xiting Yan, Taylor S Adams, Aurelien Justet, Tomokazu S. Sumida, Jiayi Zhao, Jonas C. Schupp, Micha Sam B. Raredon, Farida Ahangari, Giuseppe Deluliis, Yingze Zhang, Ivette Buendia-Roldan, Ayodeji Adegunsoye, Anne I. Sperling, Antje Prasse, Changwan Ryu, Erica Herzog, Moises Selman, Annie Pardo, Naftali Kaminski
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

Fibrotic hypersensitivity pneumonitis (FHP) is a debilitating interstitial lung disease driven by incompletely understood immune mechanisms.
Response and Resistance to Menin Inhibitor in <i>UBTF</i> –Tandem Duplication AML
Authors: Ing Soo Tiong, David S Ritchie, Piers Blombery
Journal: New England Journal of Medicine (2024)

Tandem duplication in UBTF is associated with a resistant form of AML. A menin inhibitor induced a short-lived response. Resistance was associated with mutations at the drug-binding site in MEN1, which encodes menin 1.
Measurement properties and interpretability of the Patient-Reported Impact of Dermatological Diseases (PRIDD) measure
Authors: Rachael Pattinson, Nirohshah Trialonis-Suthakharan, Tim Pickles, Jennifer Austin, Allison FitzGerald, Matthias Augustin, Christine Bundy
Journal: British Journal of Dermatology (2024)

Abstract Background Patient-reported outcome measures (PROMs) are crucial in assessing the impact of dermatological conditions on people’s lives, but the existing dermatology-specific PROMs are not recommended for use, according to COSMIN. We developed the Patient-Reported Impact of Dermatological Diseases (PRIDD) measure in partnership with patients. It has strong evidence of content validity, structural validity, internal consistency, acceptability and feasibility. Objectives To test the remaining measurement properties of the PRIDD and establish the interpretability of scores against the COSMIN criteria, using classic and modern psychometric methods. Methods A global longitudinal study consisting of two online surveys administered 2–4 weeks apart was carried out. Adults (≥ 18 years of age) living with a dermatological condition were recruited via the International Alliance of Dermatology Patient Organizations’ (GlobalSkin) membership network. Participants completed PRIDD, a demographics questionnaire and other related measures, including the Dermatology Life Quality Index. We tested the criterion validity, construct validity and responsiveness (Spearman’s ρ, independent-samples t-tests and Anova); test–retest reliability [interclass correlation coefficient (ICC)]; measurement error [smallest detectable change or limits of agreement (LoA), distribution-based minimally important change (MIC)]; floor and ceiling effects (number of minimum and maximum scores and person–item location distribution maps), score bandings (κ coefficient of agreement) and the anchor-based MIC of the PRIDD. Results In total, 504 people with 35 dermatological conditions from 38 countries participated. Criterion validity (ρ = 0.79), construct validity (76% hypotheses met), test–retest validity (ICC = 0.93) and measurement error (LoA = 1.3 &amp;lt; MIC = 4.14) were sufficient. Floor and ceiling effects were in the acceptable range (&amp;lt; 15%). Score bandings were determined (κ = 0.47); however, the anchor-based MIC could not be calculated owing to an insufficient anchor. Conclusions PRIDD is a valid and reliable tool to evaluate the impact of dermatological disease on people’s lives in research and clinical practice. It is the first dermatology-specific PROM to meet the COSMIN criteria. These results support the value of developing and validating PROMs with a patient-centred approach and using classic and modern psychometric methods. Further testing of responsiveness and MIC, cross-cultural translation, linguistic validation and global data collection are planned.
Oncogenic alterations in KIR3DL1 in cutaneous acral CD8+ lymphoproliferative disorder
Authors: Marion Wobser, Silke Appenzeller, Sabine Roth, Claudia Siedel, Matthias Goebeler, Eva Geissinger, Andreas Rosenwald, Katja Maurus
Journal: British Journal of Dermatology (2024)

Primary cutaneous acral CD8+ T-cell lymphoproliferative disorder (TLPD) is a rare and indolent lymphoma entity. Although TLPD was first identified many years ago, the molecular pathogenesis is still not fully understood.
Utilization and related harms of systemic glucocorticosteroids for atopic dermatitis: claims data analysis
Authors: Kristina Hagenström, Theresa Klinger, Katharina Müller, Charlotte Willers, Matthias Augustin
Journal: British Journal of Dermatology (2024)

Systemic glucocorticosteroids (SGCs) are used in the short-term treatment of atopic dermatitis (AD), but are not recommended for long-term use because they are associated with severe side-effects.
Dotting Out AML by Targeting Fibrillarin
Authors: Hanzhi Luo, Michael G. Kharas
Journal: Cancer Research (2024)

Dysregulated biomolecular condensates, formed through multivalent interactions among proteins and nucleic acids, have been recently identified to drive tumorigenesis. In acute myeloid leukemia (AML), condensates driven by RNA-binding proteins alter transcriptional networks. Yang and colleagues performed a CRISPR screen and identified fibrillarin (FBL) as a new driver in AML leukemogenesis. FBL depletion caused cell cycle arrest and death in AML cells, with minimal impact on normal cells. FBL's phase separation domains are essential for pre-rRNA processing, influencing AML cell survival by regulating ribosome biogenesis and the translation of oncogenic proteins like MYC. Therapeutically, the chemotherapeutic agent CGX-635 targets FBL, inducing its aggregation, impairing pre-rRNA processing, and reducing AML cell survival. This highlights FBL's phase separation as a therapeutic vulnerability in AML. These findings suggest that targeting the phase separation properties of RNA-binding proteins could offer a novel and effective strategy for AML treatment. Further research into condensate dynamics in cancer and development of condensate-modulating drugs holds significant promise for future cancer therapies.
Urticaria and the risk of cancer: a Danish population-based cohort study
Authors: Sissel B T Sørensen, Dóra K Farkas, Christian Vestergaard, Sigrun A J Schmidt, Lise Maria Lindahl, Kathryn E Mansfield, Sinead M Langan, Henrik T Sørensen
Journal: British Journal of Dermatology (2024)

Urticaria has been tentatively linked to cancer, but epidemiological evidence supporting this link is sparse and conflicting. We conducted a population-based cohort study using healthcare databases covering the Danish population (January 1980-December 2022). We followed 87 507 people for a median of 10.1 years after their first hospital contact for urticaria.
The Effect of PEEP on Pulmonary Vascular Resistance Depends on Lung Recruitability in ARDS Patients
Authors: Simone Cappio Borlino, Julien Hagry, Christopher Lai, Eduardo Rocca, Gaëlle Fouqué, Daniela Rosalba, Marta Fasan, Rui Shi, Agnese Recanatini, Irene Cisterna, Mattia Barotti, Tài Pham, Jean-Louis Teboul, Xavier Monnet
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

A U-shaped relationship should exist between lung volume and pulmonary vascular resistance (PVR), with minimal PVR at FRC. Thus, positive end-expiratory pressure (PEEP) in patients with acute respiratory distress syndrome (ARDS) should increase PVR if it induces significant lung distension compared with recruitment. However, this has never been proved in patients.
Airborne Nanoparticle Concentrations Are Associated with Increased Mortality Risk in Canada’s Two Largest Cities
Authors: Marshall Lloyd, Toyib Olaniyan, Arman Ganji, Junshi Xu, Alessya Venuta, Leora Simon, Mingqian Zhang, Milad Saeedi, Shoma Yamanouchi, An Wang, Alexandra Schmidt, Hong Chen, Paul Villeneuve, Joshua Apte, Eric Lavigne, Richard T. Burnett, Michael Tjepkema, Marianne Hatzopoulou, Scott Weichenthal
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

Outdoor fine particulate air pollution (PM2.5) contributes to millions of deaths around the world each year, but much less is known about the long-term health impacts of other particulate air pollutants including ultrafine particles (a.k.a. nanoparticles) which are in the nanometer size range (<100 nm), widespread in urban environments, and not currently regulated.
Reappraisal of the Concept and Implications of Pulmonary Hypertension in Degenerative Mitral Regurgitation
Authors: Benjamin Essayagh, Giovanni Benfari, Clemence Antoine, Francesco Grigioni, Thierry Le Tourneau, Jean-Christian Roussel, Jeroen J. Bax, Nina Ajmone Marsan, Steele C. Butcher, Christophe Tribouilloy, Dan Rusinaru, Aviram Hochstadt, Yan Topilsky, Edward El-Am, Prabin Thapa, Hector I. Michelena, Maurice Enriquez-Sarano
Journal: JACC. Cardiovascular imaging (2024)
Combining Loop and Thiazide Diuretics Across the Left Ventricular Ejection Fraction Spectrum
Authors: Marta Sánchez-Marteles, Vanesa Garcés-Horna, José Luís Morales-Rull, Jesús Casado, Margarita Carrera-Izquierdo, Alicia Conde-Martel, Melitón Francisco Dávila-Ramos, Pau Llácer, Prado Salamanca-Bautista, Raúl Ruiz, Oscar Aramburu-Bodas, Francesc Formiga, Luís Manzano, Joan Carles Trullàs
Journal: JACC Heart Failure (2024)
2-Year Outcomes of an Atrial Shunt Device in HFpEF/HFmrEF
Authors: Finn Gustafsson, Mark C Petrie, Jan Komtebedde, Vijendra Swarup, Sebastian Winkler, Gerd Hasenfuß, Barry A Borlaug, Rajeev C Mohan, James D Flaherty, Aaron L Sverdlov, Peter S Fail, Eugene S Chung, Philipp Lurz, Scott Lilly, David M Kaye, John G F Cleland, Maja Cikes, Martin B Leon, Donald E Cutlip, Dirk J van Veldhuisen, Scott D Solomon, Sanjiv J Shah
Journal: JACC Heart Failure (2024)
Randomized Trial of Cholesterol Lowering With Evolocumab for Cardiac Allograft Vasculopathy in Heart Transplant Recipients
Authors: Kaspar Broch, Karl B. Lemström, Finn Gustafsson, Hans Eiskjær, Kristjan Karason, Grunde Gjesdal, Morten W. Fagerland, Markku Pentikainen, Jyri Lommi, Einar Gude, Arne K. Andreassen, Tor S. Clemmensen, Evald H. Christiansen, Elisabeth Bjørkelund, Erlend S. Berg, Satish Arora, Lars Gullestad
Journal: JACC Heart Failure (2024)

Cardiac allograft vasculopathy is characterized by increased coronary intimal thickness and is a leading cause of death in heart transplant (HTx) recipients despite the routine use of statins. The experience with inhibitors of proprotein convertase subtilisin-kexin type 9 in HTx recipients is limited. Our hypothesis was that lowering cholesterol with the proprotein convertase subtilisin-kexin type 9inhibitor evolocumab would reduce coronary intimal thickness in these patients without compromising safety.
Vericiguat and Cardiovascular Outcomes in Heart Failure by Baseline Diabetes Status
Authors: Muhammad Shahzeb Khan, Javed Butler, Rebecca Young, Basil S. Lewis, Jorge Escobedo, Jens Refsgaard, Eugene Reyes, Lothar Roessig, Robert O. Blaustein, Carolyn S.P. Lam, Adriaan A. Voors, Piotr Ponikowski, Kevin J. Anstrom, Paul W. Armstrong
Journal: JACC Heart Failure (2024)
Prevalence and Implications of Heart Failure Stages A-D Among Patients With Chronic Kidney Disease
Authors: Amalie Johanne Lauridsen, Nino Emanuel Landler, Flemming Javier Olsen, Jacob Christensen, Mats Christian Højbjerg Lassen, Niklas Dyrby Johansen, Kristoffer Grundtvig Skaarup, Christina Christoffersen, Ellen Linnea Freese Ballegaard, Ida Maria Hjelm Sørensen, Sasha Saurbrey Bjergfelt, Susanne Bro, Bo Feldt-Rasmussen, Ditte Hansen, Tor Biering-Sørensen
Journal: JACC Heart Failure (2024)
Multistate Gene Cluster Switches Determine the Adaptive Mitochondrial and Metabolic Landscape of Breast Cancer
Authors: Michela Menegollo, Robert B. Bentham, Tiago Henriques, Seow Qi. Ng, Ziyu Ren, Clarinde Esculier, Sia Agarwal, Emily T.Y. Tong, Clement Lo, Sanjana Ilangovan, Zorka Szabadkai, Matteo Suman, Neill Patani, Avinash Ghanate, Kevin Bryson, Robert C. Stein, Mariia Yuneva, Gyorgy Szabadkai
Journal: Cancer Research (2024)

Abstract Adaptive metabolic switches are proposed to underlie conversions between cellular states during normal development as well as in cancer evolution. Metabolic adaptations represent important therapeutic targets in tumors, highlighting the need to characterize the full spectrum, characteristics, and regulation of the metabolic switches. To investigate the hypothesis that metabolic switches associated with specific metabolic states can be recognized by locating large alternating gene expression patterns, we developed a method to identify interspersed gene sets by massive correlated biclustering and to predict their metabolic wiring. Testing the method on breast cancer transcriptome datasets revealed a series of gene sets with switch-like behavior that could be used to predict mitochondrial content, metabolic activity, and central carbon flux in tumors. The predictions were experimentally validated by bioenergetic profiling and metabolic flux analysis of 13C-labeled substrates. The metabolic switch positions also distinguished between cellular states, correlating with tumor pathology, prognosis, and chemosensitivity. The method is applicable to any large and heterogeneous transcriptome dataset to discover metabolic and associated pathophysiological states. Significance: A method for identifying the transcriptomic signatures of metabolic switches underlying divergent routes of cellular transformation stratifies breast cancer into metabolic subtypes, predicting their biology, architecture, and clinical outcome.
Patterns of Aneuploidy and Signaling Consequences in Cancer
Authors: Nadja Zhakula-Kostadinova, Alison M. Taylor
Journal: Cancer Research (2024)

Abstract Aneuploidy, or a change in the number of whole chromosomes or chromosome arms, is a near-universal feature of cancer. Chromosomes affected by aneuploidy are not random, with observed cancer-specific and tissue-specific patterns. Recent advances in genome engineering methods have allowed the creation of models with targeted aneuploidy events. These models can be used to uncover the downstream effects of individual aneuploidies on cancer phenotypes including proliferation, apoptosis, metabolism, and immune signaling. Here, we review the current state of research into the patterns of aneuploidy in cancer and their impact on signaling pathways and biological processes.
Proteomics Meets Dose-Response: A New Paradigm for Deciphering Drug Effects
Authors: Chenwei Wang, Bing Zhang
Journal: Cancer Research (2024)

In a groundbreaking study, Eckert and colleagues introduce DecryptE, an innovative approach to dose-resolved proteomics that significantly advances our understanding of drug effects at the proteomic level. This method integrates cutting edge sample preparation and mass spectrometry technologies, establishing a robust platform for high-throughput proteome analysis. DecryptE enables the quantification of more than 7,000 proteins per hour and was employed to study 144 clinical drugs and research compounds, generating more than 1 million dose-response curves using Jurkat acute T-cell leukemia cells as a model system. The platform demonstrates outstanding reproducibility, ensuring reliable and consistent results across multiple experiments. By providing detailed information on drug potency and efficacy, DecryptE allows the identification of subtle changes in protein expression and facilitates the clustering of drugs based on their proteomic profiles. This study not only reveals novel drug mechanisms but also creates a comprehensive resource that can be utilized by the broader research community. Furthermore, it highlights the potential of integrating proteomics-and potentially other omics modalities in the future-with dose-response analysis to advance pharmacological research and improve therapeutic strategies.
Targeting the TRIM14/USP14 Axis Enhances Immunotherapy Efficacy by Inducing Autophagic Degradation of PD-L1
Authors: Di Liu, Mengqiu Li, Zhiyao Zhao, Liang Zhou, Feng Zhi, Zhiyong Guo, Jun Cui
Journal: Cancer Research (2024)

Immunotherapy has greatly improved cancer treatment in recent years by harnessing the immune system to target cancer cells. The first immunotherapeutic agent approved by the FDA was IFNα. Treatment with IFNα can lead to effective immune activation and attenuate tumor immune evasion, but persistent treatment has been shown to elicit immunosuppressive effects. Here, we identified an autophagy-dependent mechanism by which IFNα triggers tumor immune evasion by upregulating PD-L1 to suppress the antitumor activity of CD8+ T cells. Mechanistically, IFNα increased the transcription of TRIM14, which recruited the deubiquitinase USP14 to inhibit the autophagic degradation of PD-L1. USP14 removed K63-linked ubiquitin chains from PD-L1, impairing its recognition by the cargo receptor p62 (also known as SQSTM1) for subsequent autophagic degradation. Combining the USP14 inhibitor IU1 with IFNα and anti-CTLA4 treatment effectively suppressed tumor growth without significant toxicity. This work suggests a strategy for targeting selective autophagy to abolish PD-L1-mediated cancer immune evasion. Significance: IFNα-induced TRIM14 transcription suppresses antitumor immunity by recruiting USP14 to inhibit autophagic degradation of PD-L1, indicating that targeting this axis could be an effective immunotherapeutic approach for treating cancer.
MEK-SHP2 inhibition prevents tibial pseudarthrosis caused by <i>NF1</i> loss in Schwann cells and skeletal stem/progenitor cells
Authors: Simon Perrin, Sanela Protic, Vincent Bretegnier, Ingrid Laurendeau, Oriane Duchamp de Lageneste, Nicolas Panara, Odile Ruckebusch, Marine Luka, Cécile Masson, Théodora Maillard, Fanny Coulpier, Stéphanie Pannier, Philippe Wicart, Smail Hadj-Rabia, Katarzyna J. Radomska, Mohammed Zarhrate, Mickael Ménager, Dominique Vidaud, Piotr Topilko, Béatrice Parfait, Céline Colnot
Journal: Science Translational Medicine (2024)

Congenital pseudarthrosis of the tibia (CPT) is a severe pathology marked by spontaneous bone fractures that fail to heal, leading to fibrous nonunion. Half of patients with CPT are affected by the multisystemic genetic disorder neurofibromatosis type 1 (NF1) caused by mutations in the NF1 tumor suppressor gene, a negative regulator of RAS–mitogen-activated protein kinase (MAPK) signaling pathway. Here, we analyzed patients with CPT and Prss56-Nf1 knockout mice to elucidate the pathogenic mechanisms of CPT-related fibrous nonunion and explored a pharmacological approach to treat CPT. We identified NF1 -deficient Schwann cells and skeletal stem/progenitor cells (SSPCs) in pathological periosteum as affected cell types driving fibrosis. Whereas NF1 -deficient SSPCs adopted a fibrotic fate, NF1 -deficient Schwann cells produced critical paracrine factors including transforming growth factor–β and induced fibrotic differentiation of wild-type SSPCs. To counteract the elevated RAS-MAPK signaling in both NF1 -deficient Schwann cells and SSPCs, we used MAPK kinase (MEK) and Src homology 2 containing protein tyrosine phosphatase 2 (SHP2) inhibitors. Combined MEK-SHP2 inhibition in vivo prevented fibrous nonunion in the Prss56-Nf1 knockout mouse model, providing a promising therapeutic strategy for the treatment of fibrous nonunion in CPT.