tbuckley/cabot-search huggingface dataset:
<i>In situ</i> vaccination caused by diverse irradiation-driven cell death programs
Authors: Yijun Wang, Yan Li, Yuxin Yang, Michelle Swift, Zhenyu Zhang, Shuhui Wu, Yajie Sun, Kunyu Yang
Journal: Theranostics (2024)

Interest surrounding the effect of irradiation on immune activation has exponentially grown within the last decade.This includes work regarding mechanisms of the abscopal effect and the success achieved by combination of radiotherapy and immunotherapy.It is hypothesized that irradiation triggers the immune system to eliminate tumors by inducing tumor cells immunogenic cell death (ICD) in tumor cells.Activation of the ICD pathways can be exploited as an in situ vaccine.In this review, we provide fundamental knowledge of various forms of ICD caused by irradiation, describe the relationship between various cell death pathways and the immune activation effect driven by irradiation, and focus on the therapeutic value of exploiting these cell death programs in the context of irradiation.Furthermore, we summarize the immunomodulatory effect of different cell death programs on combinative radiotherapy and immunotherapy.In brief, differences in cell death programs significantly impact the irradiation-induced immune activation effect.Evaluating the transition between them will provide clues to develop new strategies for radiotherapy and its combination with immunotherapy.
Understanding AAV vector immunogenicity: from particle to patient
Authors: Bijay P. Dhungel, Ian Winburn, Candida da Fonseca Pereira, Kui Huang, Amit Chhabra, John E. J. Rasko
Journal: Theranostics (2024)

Gene therapy holds promise for patients with inherited monogenic disorders, cancer, and rare genetic diseases.Naturally occurring adeno-associated virus (AAV) offers a well-suited vehicle for clinical gene transfer due to its lack of significant clinical pathogenicity and amenability to be engineered to deliver therapeutic transgenes in a variety of cell types for long-term sustained expression.AAV has been bioengineered to produce recombinant AAV (rAAV) vectors for many gene therapies that are approved or in late-stage development.However, ongoing challenges hamper wider use of rAAV vector-mediated therapies.These include immunity against rAAV vectors, limited transgene packaging capacity, sub-optimal tissue transduction, potential risks of insertional mutagenesis and vector shedding.This review focuses on aspects of immunity against rAAV, mediated by anti-AAV neutralizing antibodies (NAbs) arising after natural exposure to AAVs or after rAAV vector administration.We provide an in-depth analysis of factors determining AAV seroprevalence and examine clinical approaches to managing anti-AAV NAbs pre-and post-vector administration.Methodologies used to quantify anti-AAV NAb levels and strategies to overcome pre-existing AAV immunity are also discussed.The broad adoption of rAAV vector-mediated gene therapies will require wider clinical appreciation of their current limitations and further research to mitigate their impact.
Brain‐Decellularized ECM‐Based 3D Myeloid Sarcoma Platform: Mimicking Adaptive Phenotypic Alterations in the Brain
Authors: Heejeong Yoon, Joo H. Kang, Seung Woo Cho, Chun Gwon Park, Dong‐Wook Kim, Tae‐Eun Park
Journal: Advanced Healthcare Materials (2024)

Abstract Leukemia circulates in the bloodstream and induces various symptoms and complications. Occasionally, these cells accumulate in non‐marrow tissues, forming a tumor‐like myeloid sarcoma (MS). When the blast‐stage leukemia cells invade the brain parenchyma, intracranial MS occurs, leading to a challenging prognosis owing to the limited penetration of cytostatic drugs into the brain and the development of drug resistance. The scarcity of tissue samples from MS makes understanding the phenotypic changes occurring in leukemia cells within the brain environment challenging, thereby hindering development of effective treatment strategies for intracranial MS. This study presents a novel 3D in vitro model mimicking intracranial MS, employing a hydrogel scaffold derived from the brain‐decellularized extracellular matrix in which suspended leukemia cells are embedded, simulating the formation of tumor masses in the brain parenchyma. This model reveals marked phenotypic changes in leukemia cells, including altered survival, proliferation, differentiation, and cell cycle regulation. Notably, proportion of dormant leukemia stem cells increases and expression of multidrug resistance genes is upregulated, leading to imatinib resistance, mirroring the pathological features of in vivo MS tissue. Furthermore, suppression of ferroptosis is identified as an important characteristic of intracranial MS, providing valuable insights for the development of targeted therapeutic strategies.
Oncologic outcomes of screen-detected and non-screen-detected T1 colorectal cancers
Authors: Miangela M. Laclé, Leon M. G. Moons, Lisa van der Schee, Krijn J. C. Haasnoot, Sjoerd G. Elias, Kim M. Gijsbers, Yasser A. Alderlieste, Yara Backes, Anne-Marie van Berkel, Femke Boersma, Frank ter Borg, Emilie C.H. Breekveldt, Koen Kessels, Miriam Koopman, Iris Lansdorp-Vogelaar, Monique E. van Leerdam, Gertjan Rasschaert, Ramon-Michel Schreuder, Ruud W.M. Schrauwen, Tom C.J. Seerden, Marcel B.W. Spanier, Jochim S. Terhaar sive Droste, Esther Toes-Zoutendijk, Jurriaan B. Tuynman, Geraldine R. Vink, Wouter H. de Vos tot Nederveen Cappel, Frank P. Vleggaar
Journal: Endoscopy (2024)

The incidence of T1 colorectal cancer (CRC) has increased with the implementation of CRC screening programs. It is unknown whether the outcomes and risk models for T1 CRC based on non-screen-detected patients can be extrapolated to screen-detected T1 CRC. This study aimed to compare the stage distribution and oncologic outcomes of T1 CRC patients within and outside the screening program.
Persistent SARS-CoV-2 infection: significance and implications
Authors: Heather M Machkovech, Anne M Hahn, Jacqueline Garonzik Wang, Nathan D Grubaugh, Peter J Halfmann, Marc C Johnson, Jacob E Lemieux, David H O'Connor, Anne Piantadosi, Wanting Wei, Thomas C Friedrich
Journal: The Lancet Infectious Diseases (2024)

SARS-CoV-2 causes persistent infections in a subset of individuals, which is a major clinical and public health problem that should be prioritised for further investigation for several reasons. First, persistent SARS-CoV-2 infection often goes unrecognised, and therefore might affect a substantial number of people, particularly immunocompromised individuals. Second, the formation of tissue reservoirs (including in non-respiratory tissues) might underlie the pathophysiology of the persistent SARS-CoV-2 infection and require new strategies for diagnosis and treatment. Finally, persistent SARS-CoV-2 replication, particularly in the setting of suboptimal immune responses, is a possible source of new, divergent virus variants that escape pre-existing immunity on the individual and population levels. Defining optimal diagnostic and treatment strategies for patients with persistent virus replication and monitoring viral evolution are therefore urgent medical and public health priorities.
Pharmacological innovation and clinical value of VV116
Authors: Mengxi Jiang, Yuan Gao, Zhongjie Hu
Journal: The Lancet Infectious Diseases (2024)

In their Comment, Robert L Gottlieb and Roger Paredes stated "deuteration is merely an artistic flourish, inconsequential to antiviral pharmacology. The drug would have the same effect regardless of deuteration."1 This perspective, we argue, overlooks the importance of deuteration in the context of VV116. Herein, we aim to elucidate the development of VV116 while emphasising the clinical advantages conferred by its strategic deuteration.
A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis
Authors: Stephen A. Harrison, Pierre Bedossa, Cynthia D. Guy, Jörn M. Schattenberg, Rohit Loomba, Rebecca Taub, Dominic Labriola, Sam E. Moussa, Guy W. Neff, Mary E. Rinella, Quentin M. Anstee, Manal F. Abdelmalek, Zobair Younossi, Seth J. Baum, Sven Francque, Michael R. Charlton, Philip N. Newsome, Nicolas Lanthier, Ingolf Schiefke, Alessandra Mangia, Juan M. Pericàs, Rashmee Patil, Arun J. Sanyal, Mazen Noureddin, Meena B. Bansal, Naim Alkhouri, Laurent Castera, Madhavi Rudraraju, Vlad Ratziu
Journal: New England Journal of Medicine (2024)

Nonalcoholic steatohepatitis (NASH) is a progressive liver disease with no approved treatment. Resmetirom is an oral, liver-directed, thyroid hormone receptor beta–selective agonist in development for the treatment of NASH with liver fibrosis. Download a PDF of the Research Summary. We are conducting an ongoing phase 3 trial involving adults with biopsy-confirmed NASH and a fibrosis stage of F1B, F2, or F3 (stages range from F0 [no fibrosis] to F4 [cirrhosis]). Patients were randomly assigned in a 1:1:1 ratio to receive once-daily resmetirom at a dose of 80 mg or 100 mg or placebo. The two primary end points at week 52 were NASH resolution (including a reduction in the nonalcoholic fatty liver disease [NAFLD] activity score by ≥2 points; scores range from 0 to 8, with higher scores indicating more severe disease) with no worsening of fibrosis, and an improvement (reduction) in fibrosis by at least one stage with no worsening of the NAFLD activity score. Overall, 966 patients formed the primary analysis population (322 in the 80-mg resmetirom group, 323 in the 100-mg resmetirom group, and 321 in the placebo group). NASH resolution with no worsening of fibrosis was achieved in 25.9% of the patients in the 80-mg resmetirom group and 29.9% of those in the 100-mg resmetirom group, as compared with 9.7% of those in the placebo group (P<0.001 for both comparisons with placebo). Fibrosis improvement by at least one stage with no worsening of the NAFLD activity score was achieved in 24.2% of the patients in the 80-mg resmetirom group and 25.9% of those in the 100-mg resmetirom group, as compared with 14.2% of those in the placebo group (P<0.001 for both comparisons with placebo). The change in low-density lipoprotein cholesterol levels from baseline to week 24 was −13.6% in the 80-mg resmetirom group and −16.3% in the 100-mg resmetirom group, as compared with 0.1% in the placebo group (P<0.001 for both comparisons with placebo). Diarrhea and nausea were more frequent with resmetirom than with placebo. The incidence of serious adverse events was similar across trial groups: 10.9% in the 80-mg resmetirom group, 12.7% in the 100-mg resmetirom group, and 11.5% in the placebo group. Both the 80-mg dose and the 100-mg dose of resmetirom were superior to placebo with respect to NASH resolution and improvement in liver fibrosis by at least one stage. (Funded by Madrigal Pharmaceuticals; MAESTRO-NASH ClinicalTrials.gov number, NCT03900429.) QUICK TAKE VIDEO SUMMARYResmetirom for NASH with Liver Fibrosis 02:17
Neurovascular Complications of Iatrogenic <i>Fusarium solani</i> Meningitis
Authors: Nora Strong, Grant Meeks, Sunil A Sheth, Louise McCullough, Julian A Villalba, Chunfeng Tan, Andrew Barreto, Audrey Wanger, Michelle McDonald, Peter Kan, Hashem Shaltoni, Jose Campo Maldonado, Victoria Parada, Ameer E Hassan, Sarah Reagan-Steiner, Tom Chiller, Jeremy A W Gold, Dallas J Smith, Luis Ostrosky-Zeichner
Journal: New England Journal of Medicine (2024)

SummaryA multinational outbreak of nosocomial fusarium meningitis occurred among immunocompetent patients who had undergone surgery with epidural anesthesia in Mexico. The pathogen involved had a high predilection for the brain stem and vertebrobasilar arterial system and was associated with high mortality from vessel injury. Effective treatment options remain limited; in vitro susceptibility testing of the organism suggested that it is resistant to all currently approved antifungal medications in the United States. To highlight the severe complications associated with fusarium infection acquired in this manner, we report data, clinical courses, and outcomes from 13 patients in the outbreak who presented with symptoms after a median delay of 39 days.
Ischemic Retinopathy from Prolonged Orbital Compression
Authors: Yung-Kang Chen, Ching-Lung Chen
Journal: New England Journal of Medicine (2024)

A man presented with acute vision loss and pain in the left eye after he had passed out for 3 hours in a position that put pressure on the eye. Proptosis and complete ophthalmoplegia of the left eye were present (shown in a video).
Psoriasis — More Progress but More Questions
Authors: Joel M Gelfand
Journal: New England Journal of Medicine (2024)

Psoriasis is a chronic inflammatory disease that affects more than 60 million persons worldwide and is characterized by red, scaly plaques that itch, crack, and bleed. Any area of the skin can be affected, with the scalp, genitals, palms, and soles being especially burdensome. The disease course is varied; approximately 20% of patients have moderate-to-severe cutaneous involvement, and among those patients, inflammatory arthritis develops in approximately 30%. Advances in genetics, immunology, and epidemiology have redefined psoriasis — previously thought to be "just a skin disease" — as a systemic condition associated with obesity, diabetes, major cardiovascular events, and a life . . .
Selective Agonists of Thyroid Hormone Receptor Beta for the Treatment of NASH
Authors: Kenneth Cusi
Journal: New England Journal of Medicine (2024)

Nonalcoholic fatty liver disease (NAFLD) is a common condition associated with cirrhosis and hepatocellular carcinoma, affecting approximately 70% of people with obesity or type 2 diabetes.1 In the absence of approved pharmacotherapies, current guidelines1-3 recommend reversing nonalcoholic steatohepatitis (NASH) by targeting obesity or type 2 diabetes, either with weight loss from lifestyle intervention and the use of glucagon-like peptide-1 (GLP-1) receptor agonists or with the treatment of type 2 diabetes with an insulin sensitizer such as pioglitazone.1-3 Thyroid hormone modulates hepatic glucose and lipid metabolism.1 Hypothyroidism is associated with steatosis, although its role in steatohepatitis is difficult to separate from . . .
Crenolanib and Intensive Chemotherapy in Adults With Newly Diagnosed FLT3-Mutated AML
Authors: Eunice S. Wang, Aaron D. Goldberg, Martin Tallman, Roland B. Walter, Chatchada Karanes, Karamjeet Sandhu, Carlos E. Vigil, Robert Collins, Vinay Jain, Richard M. Stone
Journal: Journal of Clinical Oncology (2024)

Crenolanib is a second-generation tyrosine kinase inhibitor with activity against
Improved Glycemic Outcomes With Diabetes Technology Use Independent of Socioeconomic Status in Youth With Type 1 Diabetes
Authors: Kate E. Lomax, Craig E. Taplin, Mary B. Abraham, Grant J. Smith, Aveni Haynes, Ella Zomer, Katrina L. Ellis, Helen Clapin, Sophia Zoungas, Alicia J. Jenkins, Jennifer Harrington, Martin I. de Bock, Timothy W. Jones, Elizabeth A. Davis, Kym Anderson, Sof Andrikopoulos, Geoff Ambler, Helen Barrett, Jenny Batch, Philip Bergman, Fergus Cameron, Louise Conwell, Andrew Cotterill, Chris Cooper, Jennifer Couper, Maria Craig, Elizabeth Davis, Martin de Bock, Jan Fairchild, Gerry Fegan, Spiros Fourlanos, Sarah Glastras, Peter Goss, Leonie Gray, Peter Shane Hamblin, Paul Hofman, Dianne Jane Holmes-Walker, Tony Huynh, Sonia Isaacs, Craig Jefferies, Stephanie Johnson, Tim Jones, Jeff Kao, Bruce R. King, Antony Lafferty, Jane Makin, Michelle Martin, Robert McCrossin, Kris Neville, Mark Pascoe, Ryan Paul, Dorota Pawlak, Alexia Peña, Liza Phillips, Darrell Price, Christine Rodda, David Simmons, Richard Sinnott, Carmel Smart, Anthony Stell, Monique Stone, Steve Stranks, Elaine Tham, Barbara Waddell, Glenn Ward, Ben Wheeler, Helen Woodhead, Anthony Zimmermann
Journal: Diabetes Care (2024)

OBJECTIVE Technology use in type 1 diabetes (T1D) is impacted by socioeconomic status (SES). This analysis explored relationships between SES, glycemic outcomes, and technology use. RESEARCH DESIGN AND METHODS A cross-sectional analysis of HbA1c data from 2,822 Australian youth with T1D was undertaken. Residential postcodes were used to assign SES based on the Index of Relative Socio-Economic Disadvantage (IRSD). Linear regression models were used to evaluate associations among IRSD quintile, HbA1c, and management regimen. RESULTS Insulin pump therapy, continuous glucose monitoring, and their concurrent use were associated with lower mean HbA1c across all IRSD quintiles (P &amp;lt; 0.001). There was no interaction between technology use and IRSD quintile on HbA1c (P = 0.624), reflecting a similar association of lower HbA1c with technology use across all IRSD quintiles. CONCLUSIONS Technology use was associated with lower HbA1c across all socioeconomic backgrounds. Socioeconomic disadvantage does not preclude glycemic benefits of diabetes technologies, highlighting the need to remove barriers to technology access.
Echocardiographic Evaluation of Left Ventricular Filling Pressure in Patients With Pulmonary Hypertension
Authors: Katsuji Inoue, Oyvind S. Andersen, Espen W. Remme, Faraz H. Khan, Arne K. Andreassen, Helge Skulstad, Einar Gude, Otto A. Smiseth
Journal: JACC. Cardiovascular imaging (2024)
Type 2–polarized memory B cells hold allergen-specific IgE memory
Authors: Joshua F. E. Koenig, Niels Peter H. Knudsen, Allyssa Phelps, Kelly Bruton, Ilka Hoof, Gitte Lund, Danielle Della Libera, Anders Lund, Lars Harder Christensen, David R. Glass, Tina D. Walker, Allison Fang, Susan Waserman, Manel Jordana, Peter S. Andersen
Journal: Science Translational Medicine (2024)

Allergen-specific immunoglobulin E (IgE) antibodies mediate pathology in diseases such as allergic rhinitis and food allergy. Memory B cells (MBCs) contribute to circulating IgE by regenerating IgE-producing plasma cells upon allergen encounter. Here, we report a population of type 2–polarized MBCs defined as CD23 hi , IL-4Rα hi , and CD32 low at both the transcriptional and surface protein levels. These MBC2s are enriched in IgG1- and IgG4-expressing cells while constitutively expressing germline transcripts for IgE. Allergen-specific B cells from patients with allergic rhinitis and food allergy were enriched in MBC2s. Furthermore, MBC2s generated allergen-specific IgE during sublingual immunotherapy, thereby identifying these cells as a major reservoir for IgE. The identification of MBC2s provides insights into the maintenance of IgE memory, which is detrimental in allergic diseases but could be beneficial in protection against venoms and helminths.
Exonic knockout and knockin gene editing in hematopoietic stem and progenitor cells rescues RAG1 immunodeficiency
Authors: Maria Carmina Castiello, Chiara Brandas, Samuele Ferrari, Simona Porcellini, Nicolò Sacchetti, Daniele Canarutto, Elena Draghici, Ivan Merelli, Matteo Barcella, Gabriele Pelosi, Valentina Vavassori, Angelica Varesi, Aurelien Jacob, Serena Scala, Luca Basso Ricci, Marianna Paulis, Dario Strina, Martina Di Verniere, Lucia Sergi Sergi, Marta Serafini, Steven M. Holland, Jenna R. E. Bergerson, Suk See De Ravin, Harry L. Malech, Francesca Pala, Marita Bosticardo, Chiara Brombin, Federica Cugnata, Enrica Calzoni, Gay M. Crooks, Luigi D. Notarangelo, Pietro Genovese, Luigi Naldini, Anna Villa
Journal: Science Translational Medicine (2024)

Recombination activating genes ( RAGs ) are tightly regulated during lymphoid differentiation, and their mutations cause a spectrum of severe immunological disorders. Hematopoietic stem and progenitor cell (HSPC) transplantation is the treatment of choice but is limited by donor availability and toxicity. To overcome these issues, we developed gene editing strategies targeting a corrective sequence into the human RAG1 gene by homology-directed repair (HDR) and validated them by tailored two-dimensional, three-dimensional, and in vivo xenotransplant platforms to assess rescue of expression and function. Whereas integration into intron 1 of RAG1 achieved suboptimal correction, in-frame insertion into exon 2 drove physiologic human RAG1 expression and activity, allowing disruption of the dominant-negative effects of unrepaired hypomorphic alleles. Enhanced HDR-mediated gene editing enabled the correction of human RAG1 in HSPCs from patients with hypomorphic RAG1 mutations to overcome T and B cell differentiation blocks. Gene correction efficiency exceeded the minimal proportion of functional HSPCs required to rescue immunodeficiency in Rag1 –/– mice, supporting the clinical translation of HSPC gene editing for the treatment of RAG1 deficiency.
Intracellular <i>Pseudomonas aeruginosa</i> within the Airway Epithelium of Cystic Fibrosis Lung Tissues
Authors: Karim Malet, Emmanuel Faure, Damien Adam, Jannik Donner, Lin Liu, Sarah-Jeanne Pilon, Richard Fraser, Peter Jorth, Dianne K. Newman, Emmanuelle Brochiero, Simon Rousseau, Dao Nguyen
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

Rationale: Pseudomonas aeruginosa (P.a.) is the major bacterial pathogen colonizing the airways of adult cystic fibrosis (CF) patients and causes chronic infections that persist despite antibiotic therapy. Intracellular bacteria may represent an unrecognized reservoir of bacteria that evades the immune system and antibiotic therapy. While the ability of P.a. to invade and survive within epithelial cells has been described in vitro in different epithelial cell models, evidence of this intracellular lifestyle in human lung tissues is currently lacking. Objectives: To detect and characterize intracellular P.a. in CF airway epithelium from human lung explant tissues. Methods: We sampled the lung explant tissues from CF patients undergoing lung transplantation and non-CF lung donor control. We analyzed lung tissue sections for the presence of intracellular P.a. by quantitative culture and microscopy, in parallel to histopathology and airway morphometry. Measurements and Main Results: P.a. was isolated from the lungs of 7 CF patients undergoing lung transplantation. Microscopic assessment revealed the presence of intracellular P.a. within airway epithelial cells in 3 out of the 7 patients analyzed, at a varying but low frequency. We observed those events occurring in lung regions with high bacterial burden. Conclusion: This is the first study describing the presence of intracellular P.a. in CF lung tissues. While intracellular P.a. in airway epithelial cells are likely relatively rare events, our findings highlight the plausible occurrence of this intracellular bacterial reservoir in chronic CF infections.
DRAK2 suppresses autophagy by phosphorylating ULK1 at Ser <sup>56</sup> to diminish pancreatic β cell function upon overnutrition
Authors: Yuting Lu, Junyu Xu, Yufeng Li, Ruoran Wang, Chengqiu Dai, Bingqian Zhang, Xinwen Zhang, Lei Xu, Yunhua Tao, Ming Han, Ren Guo, Qingqian Wu, Linshi Wu, Zhuoxian Meng, Minjia Tan, Jingya Li
Journal: Science Translational Medicine (2024)

Impeded autophagy can impair pancreatic β cell function by causing apoptosis, of which DAP-related apoptosis-inducing kinase-2 (DRAK2) is a critical regulator. Here, we identified a marked up-regulation of DRAK2 in pancreatic tissue across humans, macaques, and mice with type 2 diabetes (T2D). Further studies in mice showed that conditional knockout (cKO) of DRAK2 in pancreatic β cells protected β cell function against high-fat diet feeding along with sustained autophagy and mitochondrial function. Phosphoproteome analysis in isolated mouse primary islets revealed that DRAK2 directly phosphorylated unc-51–like autophagy activating kinase 1 (ULK1) at Ser 56 , which was subsequently found to induce ULK1 ubiquitylation and suppress autophagy. ULK1-S56A mutation or pharmacological inhibition of DRAK2 preserved mitochondrial function and insulin secretion against lipotoxicity in mouse primary islets, Min6 cells, or INS-1E cells. In conclusion, these findings together indicate an indispensable role of the DRAK2-ULK1 axis in pancreatic β cells upon metabolic challenge, which offers a potential target to protect β cell function in T2D.