tbuckley/cabot-search huggingface dataset:
Abstract PS18-09: Novel chimeric small molecule AC682 potently degrades estrogen receptor with oral anti-tumor efficacy superior to fulvestrant
Authors: Wei He, Hui Zhang, Lorena Perkins, Lissette Bouza, Ke Liu, Yimin Qian, Jie Fan
Journal: Cancer Research (2021)

Abstract Modulation of estrogen activity and/or synthesis has been the mainstay therapeutic strategy for estrogen receptor (ER)-positive breast cancer. Fulvestrant, which provides superior clinical benefit over aromatase inhibitors and selective ER modulators, achieves its potent ER signaling inhibition through unique ER degradation activity beyond direct antagonism. Despite this superiority, the efficacy of fulvestrant appears limited by poor drug exposure through intramuscular injection. Up to 50% of ER baseline levels remained after 6 months of fulvestrant treatment. Therefore, an oral ER degrader with optimal pharmacokinetic profile may lead to better convenience and efficacy than fulvestrant. Here we report preclinical characterization of our novel oral ER degrader development candidate, AC682, a chimeric small molecule containing both ligands of ER and E3 ligase discovered with our ACCU-Degron technology. Through engaging E3 ligase and ER simultaneously, AC682 induced potent ER degradation with a sub-nanomolar half-maximal degradation concentration (DC50) in multiple ER-positive breast cancer cell lines tested, including a tamoxifen-resistant long-term estrogen deprived (LTED) cell line and cell lines expressing clinically-relevant ESR1 variants (Y537S and D538G). Proteasome-dependent ER degradation by AC682 peaked after a few hours of treatment, resulting in diminished expression of ER-regulated genes and subsequent cell growth inhibition. In the in vivo setting, oral dosing of AC682 achieved substantial drug exposure and oral bioavailability, with well tolerance in multiple animal species. In estradiol-dependent MCF7 xenograft tumors, oral daily dosing of AC682 led to dose-dependent tumor growth inhibition/regression and concomitant tumor ER protein reduction more than 90% at study termination. In particular, 3 mg/kg oral daily dosing achieved tumor stasis. When administrated in combination with CDK4/6 inhibitor Palbociclib, AC682 showed clear synergy in both the estradiol-dependent MCF7 model and a tamoxifen-resistant MCF7 model. In a patient-derived xenograft model, which bears ESR1 Y537S mutation and is hormone-independent, AC682 significantly inhibited tumor growth whereas fulvestrant only showed weak efficacy. In conclusion, oral chimeric ER degrader AC682 demonstrated robust ER degradation and anti-tumor efficacy in preclinical models, supporting its continued investigation in the clinic. Citation Format: Wei He, Hui Zhang, Lorena Perkins, Lissette Bouza, Ke Liu, Yimin Qian, Jie Fan. Novel chimeric small molecule AC682 potently degrades estrogen receptor with oral anti-tumor efficacy superior to fulvestrant [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS18-09.
The Advantages of Medicare Advantage—Reply
Authors: Stuart M. Butler
Journal: JAMA (2021)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Deletion of Myeloid Interferon Regulatory Factor 4 (Irf4) in Mouse Model Protects against Kidney Fibrosis after Ischemic Injury by Decreased Macrophage Recruitment and Activation
Authors: Kensuke Sasaki, Andrew S. Terker, Yu Pan, Zhilian Li, Shirong Cao, Yinqiu Wang, Aolei Niu, Suwan Wang, Xiaofeng Fan, Ming-Zhi Zhang, Raymond C. Harris
Journal: Journal of the American Society of Nephrology (2021)

Significance Statement Macrophage proliferation and polarization to the M2 phenotype play a key role in AKI recovery. However, M2 macrophages also can produce profibrotic factors and their persistence may contribute to interstitial fibrosis. The authors demonstrated that mice with macrophage-specific deletion of the gene encoding IFN regulatory factor 4 (Irf4), a mediator of myeloid polarization, exhibited decreased renal fibrosis after severe AKI, in association with less-activated macrophages. Bone marrow–derived monocytes from such mice had diminished chemotactic responses, with decreased activation of the PI3 kinase/AKT pathway. Renal macrophage infiltration in response to AKI was markedly decreased in these mice and in wild-type mice with inhibition of AKT activity. These studies provide novel insights into the role of IRF4 by demonstrating its important function to mediate monocyte recruitment to injured tissue. Background AKI is characterized by abrupt and reversible kidney dysfunction, and incomplete recovery leads to chronic kidney injury. Previous studies by us and others have indicated that macrophage infiltration and polarization play key roles in recovery from AKI. The role in AKI recovery played by IFN regulatory factor 4 (IRF4), a mediator of polarization of macrophages to the M2 phenotype, is unclear. Methods We used mice with myeloid or macrophage cell–specific deletion of Irf4 (MΦ Irf4 −/− ) to evaluate Irf4’s role in renal macrophage polarization and development of fibrosis after severe AKI. Results Surprisingly, although macrophage Irf4 deletion had a minimal effect on early renal functional recovery from AKI, it resulted in decreased renal fibrosis 4 weeks after severe AKI, in association with less-activated macrophages. Macrophage Irf4 deletion also protected against renal fibrosis in unilateral ureteral obstruction. Bone marrow–derived monocytes (BMDMs) from MΦ Irf4 −/− mice had diminished chemotactic responses to macrophage chemoattractants, with decreased activation of AKT and PI3 kinase and increased PTEN expression. PI3K and AKT inhibitors markedly decreased chemotaxis in wild-type BMDMs, and in a cultured macrophage cell line. There was significant inhibition of homing of labeled Irf4 −/− BMDMs to postischemic kidneys. Renal macrophage infiltration in response to AKI was markedly decreased in MΦ Irf4 −/− mice or in wild-type mice with inhibition of AKT activity. Conclusions Deletion of Irf4 from myeloid cells protected against development of tubulointerstitial fibrosis after severe ischemic renal injury in mice, due primarily to inhibition of AKT-mediated monocyte recruitment to the injured kidney and reduced activation and subsequent polarization into a profibrotic M2 phenotype.
Association of Attention-Deficit/Hyperactivity Disorder in Childhood and Adolescence With the Risk of Subsequent Psychotic Disorder
Authors: Mikaïl Nourredine, Adrien Gering, Pierre Fourneret, Benjamin Rolland, Bruno Falissard, Michel Cucherat, Marie-Maude Geoffray, Lucie Jurek
Journal: JAMA Psychiatry (2021)

Growing evidence supports an association between attention-deficit/hyperactivity disorder (ADHD) in childhood and subsequent psychotic disorders. Both disorders share physiopathological features such as attention deficits, dopaminergic imbalance, and genetic susceptibility. However, the results of epidemiologic studies have been conflicting.
Three-Dimensional Manufacturing of Personalized Implants in Orthopedic Trauma Surgery—Feasible Future or Fake News?
Authors: Geertje A. M. Govaert, Falco Hietbrink, Koen Willemsen
Journal: JAMA Network Open (2021)

Frank F. A. IJpma, MD, PhD; Anne M. L. Meesters, MSc; Bram B. J. Merema, BSc; Kaj ten Duis, MD; Jean-Paul P. M. de Vries, MD, PhD; Hester Banierink, MD; Klaus W. Wendt, MD, PhD; Joep Kraeima, MSc, PhD; Max J. H. Witjes, MD, PhD
ArchR is a scalable software package for integrative single-cell chromatin accessibility analysis
Authors: Jeffrey M. Granja, M. Ryan Corces, Sarah E. Pierce, S. Tansu Bagdatli, Hani Choudhry, Howard Y. Chang, William J. Greenleaf
Journal: Nature Genetics (2021)

Abstract The advent of single-cell chromatin accessibility profiling has accelerated the ability to map gene regulatory landscapes but has outpaced the development of scalable software to rapidly extract biological meaning from these data. Here we present a software suite for single-cell analysis of regulatory chromatin in R (ArchR; https://www.archrproject.com/ ) that enables fast and comprehensive analysis of single-cell chromatin accessibility data. ArchR provides an intuitive, user-focused interface for complex single-cell analyses, including doublet removal, single-cell clustering and cell type identification, unified peak set generation, cellular trajectory identification, DNA element-to-gene linkage, transcription factor footprinting, mRNA expression level prediction from chromatin accessibility and multi-omic integration with single-cell RNA sequencing (scRNA-seq). Enabling the analysis of over 1.2 million single cells within 8 h on a standard Unix laptop, ArchR is a comprehensive software suite for end-to-end analysis of single-cell chromatin accessibility that will accelerate the understanding of gene regulation at the resolution of individual cells.
Targeted delivery of mycophenolic acid to the mesenteric lymph node using a triglyceride mimetic prodrug approach enhances gut-specific immunomodulation in mice
Authors: Ruby Kochappan, Enyuan Cao, Sifei Han, Luojuan Hu, Tim Quach, Danielle Senyschyn, Vilena Ivanova Ferreira, Given Lee, Nathania Leong, Garima Sharma, Shea Fern Lim, Cameron J. Nowell, Ziqi Chen, Ulrich H. von Andrian, Daniel Bonner, Justine D. Mintern, Jamie S. Simpson, Natalie L. Trevaskis, Christopher J.H. Porter
Journal: Journal of Controlled Release (2021)

The mesenteric lymph nodes (MLN) are a key site for the generation of adaptive immune responses to gut-derived antigenic material and immune cells within the MLN contribute to the pathophysiology of a range of conditions including inflammatory and autoimmune diseases, viral infections, graft versus host disease and cancer. Targeting immunomodulating drugs to the MLN may thus be beneficial in a range of conditions. This paper investigates the potential benefit of targeting a model immunosuppressant drug, mycophenolic acid (MPA), to T cells in the MLN, using a triglyceride (TG) mimetic prodrug approach. We confirmed that administration of MPA in the TG prodrug form (MPA-TG), increased lymphatic transport of MPA-related species 83-fold and increased MLN concentrations of MPA >20 fold, when compared to MPA alone, for up to 4 h in mice. At the same time, the plasma exposure of MPA and MPA-TG was similar, limiting the opportunity for systemic side effects. Confocal microscopy and flow cytometry studies with a fluorescent model prodrug (Bodipy-TG) revealed that the prodrug accumulated in the MLN cortex and paracortex at 5 and 10 h following administration and was highly associated with B cells and T cells that are found in these regions of the MLN. Finally, we demonstrated that MPA-TG was significantly more effective than MPA at inhibiting CD4+ and CD8+ T cell proliferation in the MLN of mice in response to an oral ovalbumin antigen challenge. In contrast, MPA-TG was no more effective than MPA at inhibiting T cell proliferation in peripheral LN when mice were challenged via SC administration of ovalbumin. This paper provides the first evidence of an in vivo pharmacodynamic benefit of targeting the MLN using a TG mimetic prodrug approach. The TG mimetic prodrug technology has the potential to benefit the treatment of a range of conditions where aberrant immune responses are initiated in gut-associated lymphoid tissues.
Transient Elastography Accurately Screens for Compensated Advanced Chronic Liver Disease in Patients With Ongoing or Recent Alcohol Withdrawal
Authors: Ludivine Legros, Edouard Bardou-Jacquet, Bruno Turlin, Sophie Michalak, Stéphanie Hamonic, Antonia Le Gruyer, Karim Aziz, Cynthia Lemoine, Nicole Bouvard, Jean-Jacques Chavagnat, Christine Silvain, Jacqueline Kerjean, Gérard Le Dréau, Natacha Lacave-Oberti, Frederic Oberti, Caroline Le Lan, Dominique Guyader, Romain Moirand
Journal: Clinical Gastroenterology and Hepatology (2021)

Liver stiffness measurement by transient elastography (TE) is a promising method for staging fibrosis in alcohol-related liver disease, but uncertainties remain regarding the influence of alcohol consumption and thus the ideal timing for TE performance. We evaluated the performance of TE compared with liver biopsy to exclude compensated advanced chronic liver disease (cACLD) in patients hospitalized for alcohol detoxification.Patients were recruited prospectively at 6 in-patient addiction centers in France. Eligible patients had increased aspartate aminotransferase levels, and no history or signs of overt cirrhosis. TE, histology, and biochemistry measurements were obtained within a median of 6 days after alcohol withdrawal. TE and biochemistry were repeated 1 and 2 months later.The study included 259 patients for per-protocol analysis, of whom 45 (17%) had cACLD. TE identified patients with high accuracy at inclusion and at the 1- and 2-month follow-up evaluation, with area under the curve values of 0.96 (95% CIs, 0.94-0.99), 0.96 (95% CIs, 0.92-0.99), and 0.93 (95% CIs, 0.85-1.00), respectively. In 84% of patients, cACLD was ruled out when liver stiffness was less than 10 kPa (negative predictive value, 99% (95% CIs, 98%-100%)) or ruled in when greater than 25 kPa (positive predictive value, 93% (95% CI, 83%-102%)). Algorithms based on aminotransferase levels and/or bilirubin did not add to the diagnostic performance of TE in this period. Among patients with initial liver stiffness of 10 to 25 kPa, more than half of those with no cACLD showed liver stiffness of less than 10 at 1- and 2-month follow-up testing.TE performed during the first 2 months after alcohol cessation is an excellent method for excluding alcohol-related cACLD.NCT01789008.
Perspectives of trans and gender diverse young people accessing primary care and gender-affirming medical services: Findings from Trans Pathways
Authors: Penelope Strauss, Sam Winter, Zoe Waters, Dani Wright Toussaint, Vanessa Watson, Ashleigh Lin
Journal: International Journal of Transgender Health (2021)

Increasing numbers of trans young people are seeking medical services worldwide, but there have been few qualitative investigations of the experiences of trans young people attempting to engage with these services to explore in-depth experiences of clinical interactions.
Circulating tumour DNA in patients with advanced melanoma treated with dabrafenib or dabrafenib plus trametinib: a clinical validation study
Authors: Mahrukh M Syeda, Jennifer M Wiggins, Broderick C Corless, Georgina V Long, Keith T Flaherty, Dirk Schadendorf, Paul D Nathan, Caroline Robert, Antoni Ribas, Michael A Davies, Jean Jacques Grob, Eduard Gasal, Matthew Squires, Mahtab Marker, James Garrett, Jan C Brase, David Polsky
Journal: The Lancet Oncology (2021)
Fast Stereolithography Printing of Large‐Scale Biocompatible Hydrogel Models
Authors: Nanditha Anandakrishnan, Hang Ye, Zipeng Guo, Zhaowei Chen, Kyle I. Mentkowski, Jennifer K. Lang, Nika Rajabian, Stelios T. Andreadis, Zhen Ma, Joseph A. Spernyak, Jonathan F. Lovell, Depeng Wang, Jun Xia, Chi Zhou, Ruogang Zhao
Journal: Advanced Healthcare Materials (2021)

Abstract Large size cell‐laden hydrogel models hold great promise for tissue repair and organ transplantation, but their fabrication using 3D bioprinting is limited by the slow printing speed that can affect the part quality and the biological activity of the encapsulated cells. Here a fast hydrogel stereolithography printing (FLOAT) method is presented that allows the creation of a centimeter‐sized, multiscale solid hydrogel model within minutes. Through precisely controlling the photopolymerization condition, low suction force‐driven, high‐velocity flow of the hydrogel prepolymer is established that supports the continuous replenishment of the prepolymer solution below the curing part and the nonstop part growth. The rapid printing of centimeter‐sized hydrogel models using FLOAT is shown to significantly reduce the part deformation and cellular injury caused by the prolonged exposure to the environmental stresses in conventional 3D printing methods. Embedded vessel networks fabricated through multiscale printing allows media perfusion needed to maintain the high cellular viability and metabolic functions in the deep core of the large‐sized models. The endothelialization of this vessel network allows the establishment of barrier functions. Together, these studies demonstrate a rapid 3D hydrogel printing method and represent a first step toward the fabrication of large‐sized engineered tissue models.
‘SMASH’ recommendations for standardised microscopic arthritis scoring of histological sections from inflammatory arthritis animal models
Authors: Silvia Hayer, Margriet J Vervoordeldonk, Maria C Denis, Marietta Armaka, Markus Hoffmann, Johan Bäcklund, Kutty Selva Nandakumar, Birgit Niederreiter, Christina Geka, Anita Fischer, Nina Woodworth, Stephan Blüml, George Kollias, Rikard Holmdahl, Florence Apparailly, Marije I Koenders
Journal: Annals of the Rheumatic Diseases (2021)

Animal models for inflammatory arthritides such as rheumatoid arthritis (RA) and psoriatic arthritis are widely accepted and frequently used to identify pathological mechanisms and validate novel therapeutic strategies. Unfortunately, many publications reporting on these animal studies lack detailed description and appropriate assessment of the distinct histopathological features of arthritis: joint inflammation, cartilage damage and bone erosion. Therefore, the European consortium BeTheCure, consisting of 38 academic and industrial partners from 15 countries, set as goal to standardise the histological evaluation of joint sections from animal models of inflammatory arthritis. The consensual approach of a task force including 16 academic and industrial scientists as well as laboratory technicians has resulted in the development of the Standardised Microscopic Arthritis Scoring of Histological sections ('SMASH') recommendations for a standardised processing and microscopic scoring of the characteristic histopathological features of arthritis, exemplified by four different rodent models for arthritis: murine collagen-induced arthritis, collagen-antibody-induced arthritis, human tumour necrosis factor transgenic Tg197 mice and rat pristane-induced arthritis, applicable to any other inflammatory arthritis model. Through standardisation, the SMASH recommendations are designed to improve and maximise the information derived from in vivo arthritis experiments and to promote reproducibility and transparent reporting on such studies. In this manuscript, we will discuss and provide recommendations for analysis of histological joint sections: identification of the regions of interest, sample preparation, staining procedures and quantitative scoring methods. In conclusion, awareness of the different features of the arthritis pathology in animal models of inflammatory arthritis is of utmost importance for reliable research outcome, and the standardised histological processing and scoring methods in these SMASH recommendations will help increase uniformity and reproducibility in preclinical research on inflammatory arthritis.
New insights into atypical Alzheimer's disease in the era of biomarkers
Authors: Jonathan Graff-Radford, Keir X X Yong, Liana G Apostolova, Femke H Bouwman, Maria Carrillo, Bradford C Dickerson, Gil D Rabinovici, Jonathan M Schott, David T Jones, Melissa E Murray
Journal: The Lancet Neurology (2021)
SIRT3-mediated deacetylation of NLRC4 promotes inflammasome activation
Authors: Chenyang Guan, Xian Huang, Jinnan Yue, Hongrui Xiang, Samina Shaheen, Zhenyan Jiang, Yuexiao Tao, Jun Tu, Zhenshan Liu, Yufeng Yao, Wen Yang, Zhaoyuan Hou, Junling Liu, Xiao-Dong Yang, Qiang Zou, Bing Su, Zhiduo Liu, Jun Ni, Jinke Cheng, Xuefeng Wu
Journal: Theranostics (2021)

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Impact of cancer evolution on immune surveillance and checkpoint inhibitor response
Authors: Yin Wu, Dhruva Biswas, Charles Swanton
Journal: Seminars in Cancer Biology (2021)

Intratumour heterogeneity (ITH) is pervasive across all cancers studied and may provide the evolving tumour multiple routes to escape immune surveillance. Immune checkpoint inhibitors (CPIs) are rapidly becoming standard of care for many cancers. Here, we discuss recent work investigating the influence of ITH on patient response to immune checkpoint inhibitor (CPI) therapy. At its simplest, ITH may confound the diagnostic accuracy of predictive biomarkers used to stratify patients for CPI therapy. Furthermore, ITH is fuelled by mechanisms of genetic instability that can both engage immune surveillance and drive immune evasion. A greater appreciation of the interplay between ITH and the immune system may hold the key to increasing the proportion of patients experiencing durable responses from CPI therapy.
Abstract SP113: The making of an ADC
Authors: PWHI Parren
Journal: Cancer Research (2021)

Abstract Targeted treatment using antibody therapeutics has proved successful for the development of meaningful treatments in diverse therapeutic areas. However, despite strong advances, many patients still fail to respond or become resistant to targeted treatment and novel innovative approaches to improve therapy are therefore required. Genetic and chemical engineering of antibodies, fueled by recent molecular insights, is providing important opportunities for the development of more potent antibody therapeutics. Antibody-drug conjugates (ADC), which combine the tumor-targeting capacity of monoclonal antibodies with the antitumor activity of cytotoxic agents, received much attention. In the road-map to developing an ADC, understanding target biology and selecting the most optimal antibody, linker and toxic payload represent critical parameters. This talk will provide an overview of this thought process in the context of the development of two ADCs currently in the clinic, tisotumab vedotin and enapotamab vedotin. Citation Format: PWHI Parren. The making of an ADC [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr SP113.