tbuckley/cabot-search huggingface dataset:
GLUT1 overexpression enhances CAR T cell metabolic fitness and anti-tumor efficacy
Authors: Yuzhe Shi, Ivan S Kotchetkov, Anton Dobrin, Sophie A Hanina, Vinagolu K Rajasekhar, John H Healey, Michel Sadelain
Journal: Molecular Therapy (2024)

The tumor microenvironment presents many obstacles to effective chimeric antigen receptor (CAR) T cell therapy, including glucose competition from tumor and myeloid cells. Using mouse models of acute lymphoblastic leukemia (ALL), renal cell carcinoma (RCC), and glioblastoma (GBM), we show that enforced expression of the glucose transporter GLUT1 enhances anti-tumor efficacy and promotes favorable CAR-T cell phenotypes for two clinically relevant CAR designs, 19-28z and IL13Rα2-BBz. In the NALM6 ALL model, 19-28z-GLUT1 promotes T stem cell-like memory formation and prolongs survival. RNA sequencing of these CAR-T cells reveals that the overexpression of GLUT1, but not GLUT3, enriches for genes involved in glycolysis, mitochondrial respiration, and memory precursor phenotypes. Extending these data, 19-28z-GLUT1 CAR-T cells improve tumor control and response to rechallenge in an RCC patient-derived xenograft model. Furthermore, IL13Rα2-BBz CAR-T cells overexpressing GLUT1 prolong the survival of mice bearing orthotopic GBMs and exhibit decreased exhaustion markers. This novel engineering approach can offer a competitive advantage to CAR-T cells in harsh tumor environments where glucose is limiting.
FDA Approval Summary: Ciltacabtagene Autoleucel for Relapsed or Refractory Multiple Myeloma
Authors: Kavita Natrajan, Megha Kaushal, Bindu George, Bindu Kanapuru, Marc R. Theoret
Journal: Clinical Cancer Research (2024)

In February 2022, the FDA approved ciltacabtagene autoleucel, a chimeric antigen receptor (CAR) T-cell therapy targeting the B-cell maturation antigen, for adult patients with relapsed/refractory multiple myeloma after ≥4 lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. Approval was based on overall response rate (ORR), complete response (CR) rate, and duration of response (DoR) in 97 adult patients in a single-arm, open-label, multicenter phase 2 trial (CARTITUDE-1 [NCT03548207]). Patients received a single infusion of ciltacabtagene autoleucel, preceded by lymphodepleting chemotherapy. Of the 97 patients evaluable, ORR was 97.9% [95% confidence interval (CI), 92.7-99.7] with a stringent CR rate of 78.4% (95% CI, 68.8-86.1). After median follow-up of 18 months, the median DoR was 21.8 months (95% CI, 21.8-not estimable [NE]) in responders (PR or better) and NE (95% CI, 21.8 months-NE) in patients who achieved stringent CR. Serious adverse reactions occurred in 55% of the 97 patients evaluated for safety. Grade 3 or higher cytokine release syndrome (CRS) and neurologic toxicities occurred in 5% and 11% of the patients, respectively, leading to a Risk Evaluation and Mitigation Strategy. Neurologic toxicities included immune effector cell-associated neurologic syndrome, typically seen with CAR-T products, parkinsonism, peripheral neuropathy, cranial nerve palsies, and Guillain-Barré syndrome. One fatal case of hemophagocytic lymphohistiocytosis/macrophage activation syndrome occurred. Prolonged and recurrent grade 3 or 4 cytopenias occurred; a single patient required hematopoietic stem-cell rescue.
Overcoming barriers in biomarker testing. Letter to the Editor regarding: ‘ESMO study on the availability and accessibility of biomolecular technologies in oncology in Europe’, by A. Bayle et al.
Authors: J. García-Foncillas, D. Arnold, B. Avouac, U. Lassen, P. Laurent-Puig, J. Taieb, Å. Helland, A. Stenzinger
Journal: Annals of Oncology (2024)
Author Correction: A multi-ancestry genetic study of pain intensity in 598,339 veterans
Authors: Sylvanus Toikumo, Rachel Vickers-Smith, Zeal Jinwala, Heng Xu, Divya Saini, Emily E. Hartwell, Mirko Pavicic, Kyle A. Sullivan, Ke Xu, Daniel A. Jacobson, Joel Gelernter, Christopher T. Rentsch, Mirko Pavicic, Eli Stahl, Martin Cheatle, Hang Zhou, Stephen G. Waxman, Amy C. Justice, Rachel L. Kember, Henry R. Kranzler
Journal: Nature Medicine (2024)

In the version of the article initially published, the pipeline for the cross-ancestry meta-analysis did not accurately code some SNPs such that they were not combined despite being the same polymorphism.To fix this, we correctly annotated the rsIDs for the summary statistics from each ancestry and meta-analyzed them based on the unique rsID for each polymorphism.We also corrected all downstream analyses that used the cross-ancestry meta-analysis data.Table 1 is a summary of the major changes which have been made to the main text and Fig. 1.None of these changes changed any of our downstream analyses.These corrections have been made to the HTML and PDF versions of the article.
Multilevel Characteristics of Cumulative Symptom Burden in Young Survivors of Childhood Cancer
Authors: Madeline R. Horan, Deo Kumar Srivastava, Jaesung Choi, Kevin R. Krull, Gregory T. Armstrong, Kirsten K. Ness, Melissa M. Hudson, Justin N. Baker, I-Chan Huang
Journal: JAMA Network Open (2024)

Symptom burden and its characteristics among survivors of pediatric cancers aged 8 to 18 years remain understudied.
A 5:2 intermittent fasting regimen ameliorates NASH and fibrosis and blunts HCC development via hepatic PPARα and PCK1
Authors: Suchira Gallage, Adnan Ali, Jose Efren Barragan Avila, Nogayhan Seymen, Pierluigi Ramadori, Vera Joerke, Laimdota Zizmare, David Aicher, Indresh K Gopalsamy, Winnie Fong, Jan Kosla, Enrico Focaccia, Xin Li, Suhail Yousuf, Tjeerd Sijmonsma, Mohammad Rahbari, Katharina S Kommoss, Adrian Billeter, Sandra Prokosch, Ulrike Rothermel, Florian Mueller, Jenny Hetzer, Danijela Heide, Benjamin Schinkel, Tim Machauer, Bernd Pichler, Nisar P Malek, Thomas Longerich, Susanne Roth, Adam J Rose, Johannes Schwenck, Christoph Trautwein, Mohammad M Karimi, Mathias Heikenwalder
Journal: Cell Metabolism (2024)

The role and molecular mechanisms of intermittent fasting (IF) in non-alcoholic steatohepatitis (NASH) and its transition to hepatocellular carcinoma (HCC) are unknown. Here, we identified that an IF 5:2 regimen prevents NASH development as well as ameliorates established NASH and fibrosis without affecting total calorie intake. Furthermore, the IF 5:2 regimen blunted NASH-HCC transition when applied therapeutically. The timing, length, and number of fasting cycles as well as the type of NASH diet were critical parameters determining the benefits of fasting. Combined proteome, transcriptome, and metabolome analyses identified that peroxisome-proliferator-activated receptor alpha (PPARα) and glucocorticoid-signaling-induced PCK1 act co-operatively as hepatic executors of the fasting response. In line with this, PPARα targets and PCK1 were reduced in human NASH. Notably, only fasting initiated during the active phase of mice robustly induced glucocorticoid signaling and free-fatty-acid-induced PPARα signaling. However, hepatocyte-specific glucocorticoid receptor deletion only partially abrogated the hepatic fasting response. In contrast, the combined knockdown of Ppara and Pck1 in vivo abolished the beneficial outcomes of fasting against inflammation and fibrosis. Moreover, overexpression of Pck1 alone or together with Ppara in vivo lowered hepatic triglycerides and steatosis. Our data support the notion that the IF 5:2 regimen is a promising intervention against NASH and subsequent liver cancer.
Periprosthetic Joint Infection in Patients With Arthroplasty Undergoing Perioperative Colonoscopy
Authors: Ashley B. Anderson, Sean E. Slaven, Nora L. Watson, John P. Cody, Robert J. McGill, Benjamin K. Potter, Matthew D. Nealeigh
Journal: JAMA Network Open (2024)

Periprosthetic joint infection (PJI) is a rare but devastating complication. Most patients undergoing total joint arthroplasty (TJA) also need routine screening colonoscopy, in which transient bacteremia may be a potential source for hematogenous PJI. Patients and surgeons must decide on an optimal time span or sequence for these 2 generally elective procedures, but no such guidelines currently exist.
Variation in Oral Board Examination Accommodations Among Specialties
Authors: Dana G. Rowe, Antoinette J. Charles, Emily J. Luo, Alissa M. Arango, James E. Herndon, Harrison Hockenberry, Cynthia K. Shortell, C. Rory Goodwin, Melissa M. Erickson
Journal: JAMA Network Open (2024)

Board certification can have broad implications for candidates' career trajectories, and prior research has found sociodemographic disparities in pass rates. Barriers in the format and administration of the oral board examinations may disproportionately affect certain candidates.
Use of a Large Language Model to Assess Clinical Acuity of Adults in the Emergency Department
Authors: Christopher Y. K. Williams, Travis Zack, Brenda Y. Miao, Madhumita Sushil, Michelle Wang, Aaron E. Kornblith, Atul J. Butte
Journal: JAMA Network Open (2024)

The introduction of large language models (LLMs), such as Generative Pre-trained Transformer 4 (GPT-4; OpenAI), has generated significant interest in health care, yet studies evaluating their performance in a clinical setting are lacking. Determination of clinical acuity, a measure of a patient's illness severity and level of required medical attention, is one of the foundational elements of medical reasoning in emergency medicine.
Diabetic retinopathy is a ceramidopathy reversible by anti-ceramide immunotherapy
Authors: Tim F. Dorweiler, Arjun Singh, Aditya Ganju, Todd A. Lydic, Louis C. Glazer, Richard N. Kolesnick, Julia V. Busik
Journal: Cell Metabolism (2024)

Diabetic retinopathy is a microvascular disease that causes blindness. Using acid sphingomyelinase knockout mice, we reported that ceramide generation is critical for diabetic retinopathy development. Here, in patients with proliferative diabetic retinopathy, we identify vitreous ceramide imbalance with pathologic long-chain C16-ceramides increasing and protective very long-chain C26-ceramides decreasing. C16-ceramides generate pro-inflammatory/pro-apoptotic ceramide-rich platforms on endothelial surfaces. To geo-localize ceramide-rich platforms, we invented a three-dimensional confocal assay and showed that retinopathy-producing cytokines TNFα and IL-1β induce ceramide-rich platform formation on retinal endothelial cells within seconds, with volumes increasing 2-logs, yielding apoptotic death. Anti-ceramide antibodies abolish these events. Furthermore, intravitreal and systemic anti-ceramide antibodies protect from diabetic retinopathy in standardized rodent ischemia reperfusion and streptozotocin models. These data support (1) retinal endothelial ceramide as a diabetic retinopathy treatment target, (2) early-stage therapy of non-proliferative diabetic retinopathy to prevent progression, and (3) systemic diabetic retinopathy treatment; and they characterize diabetic retinopathy as a "ceramidopathy" reversible by anti-ceramide immunotherapy.
Gut microbial alterations in arginine metabolism determine bone mechanical adaptation
Authors: Dan Wang, Jing Cai, Qilin Pei, Zedong Yan, Feng Zhu, Zhe Zhao, Ruobing Liu, Xiangyang Guo, Tao Sun, Juan Liu, Yulan Tian, Hongbo Liu, Xi Shao, Jinghui Huang, Xiaoxia Hao, Qi Chang, Zhuojing Luo, Da Jing
Journal: Cell Metabolism (2024)
Artificial Intelligence for Emergency Care Triage—Much Promise, but Still Much to Learn
Authors: Ari B. Friedman, M. Kit Delgado, Gary E. Weissman
Journal: JAMA Network Open (2024)

Christopher Y. K. Williams, MB, BChir; Travis Zack, MD, PhD; Brenda Y. Miao, BA; Madhumita Sushil, PhD; Michelle Wang, PharmD, PhD; Aaron E. Kornblith, MD; Atul J. Butte, MD, PhD
Generation of allogenic and xenogeneic functional muscle stem cells for intramuscular transplantation
Authors: Ajda Lenardič, Seraina A. Domenig, Joel Zvick, Nicola Bundschuh, Monika Tarnowska-Sengül, Regula Furrer, Falko Noé, Christine L. Trautmann, Adhideb Ghosh, Giada Bacchin, Pjeter Gjonlleshaj, Xhem Qabrati, Evi Masschelein, Katrien De Bock, Christoph Handschin, Ori Bar-Nur
Journal: Journal of Clinical Investigation (2024)

Satellite cells, the stem cells of skeletal muscle tissue, hold a remarkable regeneration capacity and therapeutic potential in regenerative medicine. However, low satellite cell yield from autologous or donor-derived muscles hinders the adoption of satellite cell transplantation for the treatment of muscle diseases, including Duchenne muscular dystrophy (DMD). To address this limitation, here we investigated whether satellite cells can be derived in allogeneic or xenogeneic animal hosts. First, injection of CRISPR/Cas9-corrected mouse DMD-induced pluripotent stem cells (iPSCs) into mouse blastocysts carrying an ablation system of host satellite cells gave rise to intraspecies chimeras exclusively carrying iPSC-derived satellite cells. Furthermore, injection of genetically corrected DMD-iPSCs into rat blastocysts resulted in the formation of interspecies rat-mouse chimeras harboring mouse satellite cells. Remarkably, iPSC-derived satellite cells or derivative myoblasts produced in intraspecies or interspecies chimeras restored dystrophin expression in DMD mice following intramuscular transplantation, and contributed to the satellite cell pool. Collectively, this study demonstrates the feasibility of producing therapeutically competent stem cells across divergent animal species, raising the possibility of generating human muscle stem cells in large animals for regenerative medicine purposes.
Personalized Drug Screens Guide Treatment for Kids
Authors: Elie Dolgin
Journal: Cancer Discovery (2024)

Individualized drug screens were evaluated in a small, prospective study to guide treatment decisions for children with relapsed or refractory cancers, yielding enduring responses compared with standard therapies. This research highlights the potential of functional precision medicine in pediatric oncology, marking its first successful application in younger patients and encouraging wider adoption across diverse cancer types and age groups.
FLT4 causes developmental disorders of the cardiovascular and lymphovascular systems via pleiotropic molecular mechanisms
Authors: Richard M Monaghan, Richard W Naylor, Daisy Flatman, Paul R Kasher, Simon G Williams, Bernard D Keavney
Journal: Cardiovascular Research (2024)

Abstract Aims Rare, deleterious genetic variants in FLT4 are associated with Tetralogy of Fallot (TOF), the most common cyanotic congenital heart disease. The distinct genetic variants in FLT4 are also an established cause of Milroy disease, the most prevalent form of primary hereditary lymphoedema. The phenotypic features of these two conditions are non-overlapping, implying pleiotropic cellular mechanisms during development. Methods and results In this study, we show that FLT4 variants identified in patients with TOF, when expressed in primary human endothelial cells, cause aggregation of FLT4 protein in the perinuclear endoplasmic reticulum, activating proteostatic and metabolic signalling, whereas lymphoedema-associated FLT4 variants and wild-type (WT) FLT4 do not. FLT4 TOF variants display characteristic gene expression profiles in key developmental signalling pathways, revealing a role for FLT4 in cardiogenesis distinct from its role in lymphatic development. Inhibition of proteostatic signalling abrogates these effects, identifying potential avenues for therapeutic intervention. Depletion of flt4 in zebrafish caused cardiac phenotypes of reduced heart size and altered heart looping. These phenotypes were rescued with coinjection of WT human FLT4 mRNA, but incompletely or not at all by mRNA harbouring FLT4 TOF variants. Conclusion Taken together, we identify a pathogenic mechanism for FLT4 variants predisposing to TOF that is distinct from the known dominant negative mechanism of Milroy-causative variants. FLT4 variants give rise to conditions of the two circulatory subdivisions of the vascular system via distinct developmental pleiotropic molecular mechanisms.
Recent and projected incidence trends and risk of anal cancer among people with HIV in North America
Authors: Ashish A Deshmukh, Yueh-Yun Lin, Haluk Damgacioglu, Meredith Shiels, Sally B Coburn, Raynell Lang, Keri N Althoff, Richard Moore, Michael J Silverberg, Alan G Nyitray, Jagpreet Chhatwal, Kalyani Sonawane, Keith Sigel
Journal: JNCI Journal of the National Cancer Institute (2024)

Anal cancer risk is elevated among people with HIV. Recent anal cancer incidence patterns among people with HIV in the United States and Canada remain unclear. It is unknown how the incidence patterns may evolve.
Send it, receive it, quick erase it: A mouse model to decipher chemokine communication
Authors: Leen Hermans, Timothy E. O’Sullivan
Journal: The Journal of Experimental Medicine (2024)

A method to precisely determine which cells respond to chemokines in vivo is currently lacking. A novel class of dual fluorescence reporter mice could help identify cells that produce and/or sense a given chemokine in vitro and in vivo (Rodrigo et al. 2024. J. Exp. Med.https://doi.org/10.1084/jem.20231814).
Mechanical Thrombectomy in a Single Lung Transplant Recipient: A Salvage Case
Authors: Hugo Clermidy, Salim Si-Mohamed, Cyril Prieur, Claire Merveilleux du Vignaux, Philippe Douek, François Tronc
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

"Mechanical Thrombectomy in a Single Lung Transplant Recipient: A Salvage Case." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp.
Trisomy 8 Defines a Distinct Subtype of Myeloproliferative Neoplasms Driven by the MYC–Alarmin Axis
Authors: Nicole D. Vincelette, Xiaoqing Yu, Andrew T. Kuykendall, Jungwon Moon, Siyuan Su, Chia-Ho Cheng, Rinzine Sammut, Tiffany N. Razabdouski, Hai V. Nguyen, Erika A. Eksioglu, Onyee Chan, Najla Al Ali, Parth C. Patel, Dae H. Lee, Shima Nakanishi, Renan B. Ferreira, Elizabeth Hyjek, Qianxing Mo, Suzanne Cory, Harshani R. Lawrence, Ling Zhang, Daniel J. Murphy, Rami S. Komrokji, Daesung Lee, Scott H. Kaufmann, John L. Cleveland, Seongseok Yun
Journal: Blood Cancer Discovery (2024)

Abstract Despite advances in understanding the genetic abnormalities in myeloproliferative neoplasms (MPN) and the development of JAK2 inhibitors, there is an urgent need to devise new treatment strategies, particularly for patients with triple-negative (TN) myelofibrosis (MF) who lack mutations in the JAK2 kinase pathway and have very poor clinical outcomes. Here we report that MYC copy number gain and increased MYC expression frequently occur in TN-MF and that MYC-directed activation of S100A9, an alarmin protein that plays pivotal roles in inflammation and innate immunity, is necessary and sufficient to drive development and progression of MF. Notably, the MYC-S100A9 circuit provokes a complex network of inflammatory signaling that involves numerous hematopoietic cell types in the bone marrow microenvironment. Accordingly, genetic ablation of S100A9 or treatment with small molecules targeting the MYC-S100A9 pathway effectively ameliorates MF phenotypes, highlighting the MYC–alarmin axis as a novel therapeutic vulnerability for this subgroup of MPNs. Significance: This study establishes that MYC expression is increased in TN-MPNs via trisomy 8, that a MYC-S100A9 circuit manifest in these cases is sufficient to provoke myelofibrosis and inflammation in diverse hematopoietic cell types in the BM niche, and that the MYC-S100A9 circuit is targetable in TN-MPNs.
The Impact of Tobacco Smoking in Bronchiectasis: Data from the U.S. Bronchiectasis and Nontuberculous Mycobacteria Research Registry
Authors: Pamela J. McShane, Amanda E. Brunton, Radmila Choate, Meghan Marmor, Christopher J. Richards, George M. Solomon, Diego J. Maselli, Colin Swenson, Timothy R. Aksamit, Mark L. Metersky
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

"The Impact of Tobacco Smoking in Bronchiectasis: Data from the United States Bronchiectasis and NTM Research Registry." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp.
Correction: Dynamics of clonal hematopoiesis under DNA-damaging treatment in patients with ovarian cancer
Authors: Christopher Maximilian Arends, Klara Kopp, Raphael Hablesreiter, Natalia Estrada, Friederike Christen, Ute Martha Moll, Robert Zeillinger, Wolfgang Daniel Schmitt, Jalid Sehouli, Hagen Kulbe, Maximilian Fleischmann, Isabelle Ray-Coquard, Alain Zeimet, Francesco Raspagliesi, Claudio Zamagni, Ignace Vergote, Domenica Lorusso, Nicole Concin, Lars Bullinger, Elena Ioana Braicu, Frederik Damm
Journal: Leukemia (2024)
Predicting survival in patients with myelodysplastic/myeloproliferative neoplasms with SF3B1 mutation and thrombocytosis
Authors: Fuhui Li, Tiejun Qin, Bing Li, Shiqiang Qu, Lijuan Pan, Peihong Zhang, Qi Sun, Wenyu Cai, Qingyan Gao, Meng Jiao, Junjie Li, Xiaofei Ai, Jiao Ma, Robert Peter Gale, Zefeng Xu, Zhijian Xiao
Journal: Leukemia (2024)

We investigated data from 180 consecutive patients with myelodysplastic/myeloproliferative neoplasms with SF3B1 mutation and thrombocytosis (MDS/MPN-SF3B1-T) who were diagnosed according to the 2022 World Health Organization (WHO) classification of myeloid neoplasms to identify covariates associated with survival. At a median follow-up of 48 months (95% confidence interval [CI] 35-61 months), the median survival was 69 months (95% CI 59-79 months). Patients with bone marrow ring sideroblasts (RS) < 15% had shorter median overall survival (OS) than did those with bone marrow RS ≥ 15% (41 months [95% CI 32-50 months] versus 76 months [95% CI 59-93 months]; P < 0.001). According to the univariable analyses of OS, age ≥ 65 years (P < 0.001), hemoglobin concentration (Hb) < 80 g/L (P = 0.090), platelet count (PLT) ≥ 800 × 10E + 9/L (P = 0.087), bone marrow RS < 15% (P < 0.001), the Revised International Prognostic Scoring System (IPSS-R) cytogenetic category intermediate/poor/very poor (P = 0.005), SETBP1 mutation (P = 0.061) and SRSF2 mutation (P < 0.001) were associated with poor survival. Based on variables selected from univariable analyses, two separate survival prediction models, a clinical survival model, and a clinical-molecular survival model, were developed using multivariable analyses with the minimum value of the Akaike information criterion (AIC) to specifically predict outcomes in patients with MDS/MPN-SF3B1-T according to the 2022 WHO classification.
Dendritic-cell-targeting virus-like particles as potent mRNA vaccine carriers
Authors: Di Yin, Yiye Zhong, Sikai Ling, Sicong Lu, Xiaoyuan Wang, Zhuofan Jiang, Jie Wang, Yao Dai, Xiaolong Tian, Qijing Huang, Xingbo Wang, Junsong Chen, Ziying Li, Yang Li, Zhijue Xu, Hewei Jiang, Yuqing Wu, Yi Shi, Quanjun Wang, Jianjiang Xu, Wei Hong, Heng Xue, Hang Yang, Yan Zhang, Lintai Da, Ze-guang Han, Sheng-ce Tao, Ruijiao Dong, Tianlei Ying, Jiaxu Hong, Yujia Cai
Journal: Nature Biomedical Engineering (2024)
STR mutations on chromosome 15q cause thyrotropin resistance by activating a primate-specific enhancer of MIR7-2/MIR1179
Authors: Helmut Grasberger, Alexandra M. Dumitrescu, Xiao-Hui Liao, Elliott G. Swanson, Roy E. Weiss, Panudda Srichomkwun, Theodora Pappa, Junfeng Chen, Takashi Yoshimura, Phillip Hoffmann, Monica Malheiros França, Rebecca Tagett, Kazumichi Onigata, Sabine Costagliola, Jane Ranchalis, Mitchell R. Vollger, Andrew B. Stergachis, Jessica X. Chong, Michael J. Bamshad, Guillaume Smits, Gilbert Vassart, Samuel Refetoff
Journal: Nature Genetics (2024)