tbuckley/cabot-search huggingface dataset:
Disease modification in chronic spontaneous urticaria
Authors: Marcus Maurer, Pavel Kolkhir, Manuel P. Pereira, Frank Siebenhaar, Ellen Witte‐Händel, Karl‐Christian Bergmann, Hanna Bonnekoh, Thomas Buttgereit, Joachim W. Fluhr, Stefan Frischbutter, Eva Maria Grekowitz, Leonie Herzog, Lea Alice Kiefer, Karoline Krause, Markus Magerl, Melba Muñoz, Sophia Neisinger, Nicole Nojarov, Samantha Prins, Polina Pyatilova, Aisté Ramanauskaité, Jörg Scheffel, Dorothea Terhorst‐Molawi, Regina Treudler, Karsten Weller, Torsten Zuberbier, Martin Metz
Journal: Allergy (2024)

Chronic spontaneous urticaria (CSU) is a debilitating, inflammatory skin condition characterized by infiltrating immune cells. Available treatments are limited to improving the signs and symptoms. There is an unmet need to develop therapies that target disease-driving pathways upstream of mast cell activation to inhibit or delay the progression of CSU and associated comorbidities. Here, we aim to define disease modification due to a treatment intervention and criteria that disease-modifying treatments (DMTs) must meet in CSU. We have defined disease modification in CSU as a favorable treatment-induced change in the underlying pathophysiology and, therefore, the disease course, which is clinically beneficial and enduring. A DMT must fulfil the following criteria: (1) prevents or delays the progression of CSU, (2) induces long-term, therapy-free clinical remission, which is the sustained absence of CSU signs and symptoms without the need for treatment, and (3) affects the underlying mechanism of CSU, as demonstrated by an effect on disease-driving signals and/or a biomarker. DMTs in CSU should slow disease progression, achieve long-lasting disease remission, target disease-driving mechanisms, reduce mast cell-activating IgE autoantibodies, target cytokine profile polarization, and normalize the gut microbiome and barrier. Treating CSU at the immune system level could provide valuable alternatives to pharmacotherapy in CSU management. Specific DMTs in CSU are yet to be developed, but some show potential benefits, such as inhibitors of Bruton's Tyrosine Kinase, IL-4 and IL-13. Future therapies could prevent CSU signs and symptoms, achieve long-term clinical benefits after discontinuing treatment, and prevent associated concomitant disorders.
Cardiac Arrest and Cardiopulmonary Resuscitation Outcome Reports: 2024 Update of the Utstein Out-of-Hospital Cardiac Arrest Registry Template
Authors: Janet E. Bray, Jan-Thorsten Grasner, Jerry P. Nolan, Taku Iwami, Marcus E.H. Ong, Judith Finn, Bryan McNally, Ziad Nehme, Comilla Sasson, Janice Tijssen, Shir Lynn Lim, Ingvild Tjelmeland, Jan Wnent, Bridget Dicker, Chika Nishiyama, Zakary Doherty, Michelle Welsford, Gavin D. Perkins
Journal: Circulation (2024)

The Utstein Out-of-Hospital Cardiac Arrest Resuscitation Registry Template, introduced in 1991 and updated in 2004 and 2015, standardizes data collection to enable research, evaluation, and comparisons of systems of care. The impetus for the current update stemmed from significant advances in the field and insights from registry development and regional comparisons. This 2024 update involved representatives of the International Liaison Committee on Resuscitation and used a modified Delphi process. Every 2015 Utstein data element was reviewed for relevance, priority (core or supplemental), and improvement. New variables were proposed and refined. All changes were voted on for inclusion. The 2015 domains-system, dispatch, patient, process, and outcomes-were retained. Further clarity is provided for the definitions of out-of-hospital cardiac arrest attended resuscitation and attempted resuscitation. Changes reflect advancements in dispatch, early response systems, and resuscitation care, as well as the importance of prehospital outcomes. Time intervals such as emergency medical service response time now emphasize precise reporting of the times used. New flowcharts aid the reporting of system effectiveness for patients with an attempted resuscitation and system efficacy for the Utstein comparator group. Recognizing the varying capacities of emergency systems globally, the writing group provided a minimal dataset for settings with developing emergency medical systems. Supplementary variables are considered useful for research purposes. These revisions aim to elevate data collection and reporting transparency by registries and researchers and to advance international comparisons and collaborations. The overarching objective remains the improvement of outcomes for patients with out-of-hospital cardiac arrest.
Neurofilament Light Chain and Risk of Stroke in Patients With Atrial Fibrillation
Authors: Julia Aulin, Karl Sjölin, Johan Lindbäck, Alexander P. Benz, John W. Eikelboom, Ziad Hijazi, Kim Kultima, Jonas Oldgren, Lars Wallentin, Joachim Burman
Journal: Circulation (2024)

BACKGROUND: Biomarkers reflecting brain injury are not routinely used in risk assessment of stroke in atrial fibrillation (AF). Neurofilament light chain (NFL) is a novel biomarker released into blood after cerebral insults. We investigated the association between plasma concentrations of NFL, other biomarkers, and risk of stroke and death in patients with AF not receiving oral anticoagulation. METHODS: For this observational study, baseline plasma samples were available from 3077 patients with AF randomized to aspirin in ACTIVE A (Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events; 2003 to 2008) and AVERROES (Apixaban Versus Acetylsalicylic Acid [ASA] to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment; 2007 to 2009). Median follow-up was 1.5 years. NFL was analyzed with a Single Molecule Array (Simoa). Associations with outcomes (total stroke or systemic embolism, ischemic stroke, cardiovascular death, and all-cause death) were explored with Cox regression models. RESULTS: In the combined cohort, the median NFL level was 16.9 ng/L (interquartile range, 11.1–26.5 ng/L), the median age was 71 years, 58% were men, and 13% had a history of previous stroke. NFL was associated with older age, higher creatinine, lower body mass index, previous stroke, female sex, and diabetes but not cardiac rhythm. Higher NFL was associated with a higher risk of stroke or systemic embolism (n=206) independently of clinical characteristics (hazard ratio, 1.27 [95% CI, 1.10–1.46] per doubling of NFL) and other biomarkers (hazard ratio, 1.18 [95% CI, 1.01–1.37]) and including in patients without previous stroke (hazard ratio, 1.23 [95% CI, 1.02–1.48]). NFL was also independently associated with cardiovascular (n=219) and all-cause (n=311) death. The C index for stroke using only NFL was 0.642, on par with the currently used clinical risk scores. Addition of information on NFL improved discrimination in a model also including clinical information, NT-proBNP (N-terminal pro-B-type natriuretic peptide), and high-sensitivity cardiac troponin T, yielding a C index of 0.727. CONCLUSIONS: NFL reflects overt and covert episodes of cerebral ischemia and improves risk assessment of stroke and death in patients with AF without oral anticoagulation, including in patients without previous stroke. The combination of NFL with information on age, history of stroke, and other biomarkers should be explored as a future avenue for stroke risk assessments in patients with AF.
Features of HIV Infection in the Context of Long-Acting Cabotegravir Preexposure Prophylaxis
Authors: Raphael J Landovitz, Sinead Delany-Moretlwe, Jessica M Fogel, Mark A Marzinke, Estelle Piwowar-Manning, Paul Richardson, Elias K Halvas, John W Mellors, Deborah Persaud, Ryan Kofron, Marybeth McCauley, Scott Rose, Alex R Rinehart, James F Rooney, Adeola Adeyeye, Myron S Cohen, Deborah Donnell, Mina C Hosseinipour, Beatriz Grinsztejn, Susan H Eshleman
Journal: New England Journal of Medicine (2024)

Preexposure prophylaxis is emerging as an important tool to prevent HIV-1 infection. This report describes an altered presentation of acute HIV infection that may occur with use of long-acting cabotegravir PrEP.
The Real PURPOSE of PrEP — Effectiveness, Not Efficacy
Authors: Rochelle P Walensky, Lindsey R Baden
Journal: New England Journal of Medicine (2024)

Given the 40 years of research and the wealth of successful tools that have been developed to prevent, diagnose, treat, and suppress human immunodeficiency virus (HIV) infection, how is it possible that in 2024 the incidence of HIV type 1 (HIV-1) infection is more than 3.5 per 100 person-years among young women in southern Africa?1 The efficacy of preexposure prophylaxis (PrEP) to prevent HIV infection was first shown in 2010 in the landmark Preexposure Prophylaxis Initiative (iPrEx) trial of emtricitabine–tenofovir disoproxil fumarate (F/TDF), largely in men who have sex with men (MSM).2 In July 2012, the time of Food and . . .
Correction: Anti-CD5 CAR-T cells with a tEGFR safety switch exhibit potent toxicity control
Authors: Haolong Lin, Jiali Cheng, Li Zhu, Yuhao Zeng, Zhenyu Dai, Yicheng Zhang, Xiaojian Zhu, Wei Mu
Journal: Blood Cancer Journal (2024)

units of 10 7 /L.
Chemically Defined Organoid Culture System for Cholangiocyte Differentiation
Authors: Zhenguo Wang, Shicheng Ye, Luc J.W. van der Laan, Kerstin Schneeberger, Rosalinde Masereeuw, Bart Spee
Journal: Advanced Healthcare Materials (2024)

Abstract Cholangiocyte organoids provide a powerful platform for applications ranging from in vitro modeling to tissue engineering for regenerative medicine. However, their expansion and differentiation are typically conducted in animal‐derived hydrogels, which impede the full maturation of organoids into functional cholangiocytes. In addition, these hydrogels are poorly defined and complex, limiting the clinical applicability of organoids. In this study, a novel medium composition combined with synthetic polyisocyanopeptide (PIC) hydrogels to enhance the maturation of intrahepatic cholangiocyte organoids (ICOs) into functional cholangiocytes is utilized. ICOs cultured in the presence of sodium butyrate and valproic acid, a histone deacetylase inhibitor, and a Notch signaling activator, respectively, in PIC hydrogel exhibit a more mature phenotype, as evidenced by increased expression of key cholangiocyte markers, crucial for biliary function. Notably, mature cholangiocyte organoids in PIC hydrogel display apical‐out polarity, in contrast to the traditional basal‐out polarization of ICOs cultured in Matrigel. Moreover, these mature cholangiocyte organoids effectively model the biliary pro‐fibrotic response induced by transforming growth factor beta. Taken together, an animal‐free, chemically defined culture system that promotes the ICOs into mature cholangiocytes with apical‐out polarity, facilitating regenerative medicine applications and in vitro studies that require access to the apical membrane, is developed.
Mutation in Bruton Tyrosine Kinase (BTK) A428D confers resistance To BTK-degrader therapy in chronic lymphocytic leukemia
Authors: Richard L. Wong, Michael Y. Choi, Huan-You Wang, Thomas J. Kipps
Journal: Leukemia (2024)

Targeting BTK has profoundly changed the face of CLL treatment over the past decade. Iterative advances in the cat and mouse game of resistance and redesign have moved BTK inhibitors from covalent to non-covalent and now targeted protein degraders. However, contrary to the presumption that protein degraders may be impervious to mutations in BTK, we now present clinical evidence that a mutation in the kinase domain of BTK, namely A428D, can confer disease resistance to a BTK degrader currently in clinical trials, that is BGB-16673. Modeling of a BTK A428D mutation places a negatively charged aspartic acid in place of the hydrophobic side chain of alanine within the binding pocket of another BTK-degrader in clinical development, namely NX-2127, suggesting that CLL cells with BTK A428D also may be resistant to NX-2127, as they already are known to be with either non-covalent or covalent inhibitors of BTK. Consequently, the two BTK degraders furthest advanced in clinical trials potentially may select for CLL cells with BTK A428D that are resistant to all approved BTKi's.
Creatinine clearance in critically ill adults: prospective comparison of prediction by intensive care unit physicians and machine learning models
Authors: Greet De Vlieger, Chao-Yuan Huang, Brenda Pörteners, Fabian Güiza, Geert Meyfroidt, Yves Debaveye, Jan Gunst, Pieter Wouters, Liese Mebis, Joachim Gidts, Lore Klewais, Greet Van den Berghe
Journal: Intensive Care Medicine (2024)
Erratum to ‘Novel role of MHC class II transactivator in hepatitis B virus replication and viral counteraction’ [Clin Mol Hepatol 2024;30:539-560]
Authors: Mehrangiz Dezhbord, Seong Ho Kim, Soree Park, Da Rae Lee, Nayeon Kim, Juhee Won, Ah Ram Lee, Dong-Sik Kim, Kyun-Hwan Kim
Journal: Clinical and Molecular Hepatology (2024)

See the Original "Novel role of MHC class II transactivator in hepatitis B virus replication and viral counteraction" on page 539.
Ultrasensitive detection of aggregated α-synuclein using quiescent seed amplification assay for the diagnosis of Parkinson’s disease
Authors: Hengxu Mao, Yaoyun Kuang, Du Feng, Xiang Chen, Lin Lu, Wencheng Xia, Tingting Gan, Weimeng Huang, Wenyuan Guo, Hancun Yi, Yirong Yang, Zhuohua Wu, Wei Dai, Hui Sun, Jieyuan Wu, Rui Zhang, Shenqing Zhang, Xiuli Lin, Yuxuan Yong, Xinling Yang, Hongyan Li, Wenjun Wu, Xiaoyun Huang, Zhaoxiang Bian, Hoi Leong Xavier Wong, Xin-Lu Wang, Michael Poppell, Yi Ren, Cong Liu, Wen-Quan Zou, Shengdi Chen, Ping-Yi Xu
Journal: Translational Neurodegeneration (2024)

Seed amplification assays (SAA) enable the amplification of pathological misfolded proteins, including α-synuclein (αSyn), in both tissue homogenates and body fluids of Parkinson's disease (PD) patients. SAA involves repeated cycles of shaking or sonication coupled with incubation periods. However, this amplification scheme has limitations in tracking protein propagation due to repeated fragmentation.
Dorsal raphe nucleus–hippocampus serotonergic circuit underlies the depressive and cognitive impairments in 5×FAD male mice
Authors: Meiqin Chen, Chenlu Wang, Yinan Lin, Yanbing Chen, Wenting Xie, Xiaoting Huang, Fan Zhang, Congrui Fu, Kai Zhuang, Tingting Zou, Dan Can, Huifang Li, Shengxi Wu, Ceng Luo, Jie Zhang
Journal: Translational Neurodegeneration (2024)

Abstract Background Depressive symptoms often occur in patients with Alzheimer's disease (AD) and exacerbate the pathogenesis of AD. However, the neural circuit mechanisms underlying the AD-associated depression remain unclear. The serotonergic system plays crucial roles in both AD and depression. Methods We used a combination of in vivo trans-synaptic circuit-dissecting anatomical approaches, chemogenetic manipulations, optogenetic manipulations, pharmacological methods, behavioral testing, and electrophysiological recording to investigate dorsal raphe nucleus serotonergic circuit in AD-associated depression in AD mouse model. Results We found that the activity of dorsal raphe nucleus serotonin neurons (DRN 5-HT ) and their projections to the dorsal hippocampal CA1 (dCA1) terminals (DRN 5-HT -dCA1 CaMKII ) both decreased in brains of early 5×FAD mice. Chemogenetic or optogenetic activation of the DRN 5-HT -dCA1 CaMKII neural circuit attenuated the depressive symptoms and cognitive impairments in 5×FAD mice through serotonin receptor 1B (5-HT 1B R) and 4 (5-HT 4 R). Pharmacological activation of 5-HT 1B R or 5-HT 4 R attenuated the depressive symptoms and cognitive impairments in 5×FAD mice by regulating the DRN 5-HT -dCA1 CaMKII neural circuit to improve synaptic plasticity. Conclusions These findings provide a new mechanistic connection between depression and AD and provide potential pharmaceutical prevention targets for AD.
Directing B7-H3 chimeric antigen receptor T cell homing through IL-8 induces potent antitumor activity against pediatric sarcoma
Authors: Jessica A Lake, Elena Woods, Eric Hoffmeyer, Kristin L Schaller, Joselyn Cruz-Cruz, Joseph Fernandez, Dejene Tufa, Benjamin Kooiman, Spencer C Hall, Dallas Jones, Masanori Hayashi, Michael R Verneris
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Advances in pediatric oncology have occurred for some cancers; however, new therapies for sarcoma have been inadequate. Cellular immunotherapy using chimeric antigen receptor (CAR) T cells has shown dramatic benefits in leukemia, lymphoma, and multiple myeloma but has been far less successful in pediatric solid tumors such as rhabdomyosarcoma (RMS) and osteosarcoma (OS). Balancing issues of “on-target, off-tumor toxicity”, investigators have identified B7-H3 as a broadly expressed tumor antigen with otherwise restricted expression on normal tissues. We hypothesized that rapid homing via a chemokine receptor and CAR engagement through B7-H3 would enhance CAR T cell efficacy in solid tumors. Methods We generated B7-H3 CAR T cells that also express the Interleukin-8 (IL-8) receptor, CXCR2. Cytokine production, flow cytometry, Seahorse assays and RNA sequencing were used to compare the B7-H3 CXCR2 (BC2) CAR T cells with B7-H3 CAR T cells. We developed an IL-8 overexpressing human RMS mouse model to test homing and cytotoxicity in vivo. Results We demonstrate that IL-8 is expressed by RMS and OS and expression significantly increases after radiation. Overexpression of an IL-8 receptor, CXCR2, on B7-H3 CAR T cells enhances homing into IL-8 expressing tumors, augments T cell metabolism and leads to significant tumor regression. Conclusion These findings warrant further investigation into the use of BC2 CAR T cells as a treatment for patients with RMS, OS and other B7-H3-expressing, IL-8 producing solid tumors.
Impact of LAG-3/FGL1 pathway on immune evasive contexture and clinical outcomes in advanced urothelial carcinoma
Authors: Takashi Yoshida, Takahiro Nakamoto, Naho Atsumi, Chisato Ohe, Takeshi Sano, Yoshiki Yasukochi, Koji Tsuta, Hidefumi Kinoshita
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Anti-programmed death-1 (PD-1)/anti-PD-ligand-1 (PD-L1) pathway inhibition is a standard regimen for advanced urothelial carcinoma (UC); however, its limited efficacy has been reflected in reported medium response rates. This study explored the role of next-generation coinhibitory receptors (IRs; lymphocyte activation gene 3 (LAG-3), T-cell immunoglobulin and mucin domain 3 (TIM-3), and T-cell immunoreceptor with Ig and ITIM domains (TIGIT)) and their ligands (LGs) in the response to PD-(L)1 blockade therapy and the oncological outcomes in patients with UC. Methods We investigated metastatic UC cases who underwent PD-(L)1 therapy (cohort 1: n=348, cohort 2: n=89, and cohort 4: n=29) or advanced UC cases involving surgery (cohort 3: n=293 and cohort 5: n=90). We assessed the mRNA expression profiles and corresponding clinical information regarding IRs and LGs using cohorts 1, 2, and 3. Additionally, we elucidated the spatial features of these targeted markers using multiplex immunohistochemistry (mIHC) on formalin-fixed paraffin-embedded samples from cohorts 4 and 5. Survival, differential expressed gene, and Gene Set Enrichment analyses were performed. For mIHC, quantitative analyses were also performed to correlate immune and tumor cell densities with patient survival. Results LAG-3 expression was strongly associated with the responsiveness of PD-(L)1 blockade compared with the expression of TIM-3 and TIGIT . In tumors with high LAG-3 levels, the increased expression of fibrinogen-like protein 1 ( FGL1 ) had a significantly negative effect on the response to PD-(L)1 blockade and overall survival. Moreover, high FGL1 levels were associated with elevated CD4 + regulatory T-cell gene signatures and the upregulation of CD39 and neuropilin-1 , with both indicating CD8 + T-cell exhaustion. mIHC analyses revealed that patients with stromal CD8 + LAG-3 + cells high –tumor FGL1 + cells high exhibited a significant negative correlation with survival rates compared with those with stromal CD8 + LAG-3 + cells high –tumor FGL1 + cells low . Conclusions LAG-3 expression and high FGL1 coexpression are important predictive factors of adverse oncological outcomes related to the presence of immunosuppressive contextures. These findings are hypothesis-generating, warranting further mechanistic and clinical studies aimed to evaluate LAG-3/FGL1 blockade in UC.
rhIL-7-hyFc, a long-acting interleukin-7, improves efficacy of CAR-T cell therapy in solid tumors
Authors: Dan Li, Tianyuzhou Liang, Laura E Hutchins, Alexandra A Wolfarth, Sara Ferrando-Martinez, Byung Ha Lee, Mitchell Ho
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Chimeric antigen receptor T-cell (CAR-T) therapy has achieved remarkable remission in patients with B-cell malignancies. However, its efficacy in treating solid tumors remains limited. Here, we investigated a combination therapy approach using an engineered long-acting interleukin (IL)-7 (rhIL-7-hyFc or NT-I7) and CAR-T cells targeting three antigens, glypican-2 (GPC2), glypican-3 (GPC3), and mesothelin (MSLN), against multiple solid tumor types including liver cancer, neuroblastoma, ovarian cancer, and pancreatic cancer in mice. Methods CAR-T cells targeting GPC2, GPC3, and MSLN were used in combination with NT-I7 to assess the anticancer activity. Xenograft tumor models, including the liver cancer orthotopic model, were established using NOD scid gamma mice engrafted with cell lines derived from hepatocellular carcinoma, neuroblastoma, ovarian cancer, and pancreatic cancer. The mice were monitored by bioluminescence in vivo tumor imaging and tumor volume measurement using a caliper. Immunophenotyping of CAR-T cells on NT-I7 stimulation was evaluated for memory markers, exhaust markers, and T-cell signaling molecules by flow cytometry and western blotting. Results Compared with the IL-2 combination, preclinical evaluation of NT-I7 exhibited regression of solid tumors via enhanced occupancy of CD4 + CAR-T, improved T-cell expansion, reduced exhaustion markers (programmed cell death protein 1 or PD-1 and lymphocyte-activation gene 3 or LAG-3) expression, and increased generation of stem cell-like memory CAR-T cells. The STAT5 pathway was demonstrated to be downstream of NT-I7 signaling, mediated by increased expression of the IL-7 receptor expression in CAR-T cells. Furthermore, CAR-T cells improved efficacy against tumors with low antigen density when combined with NT-I7 in mice, presenting an avenue for patients with heterogeneous antigenic profiles. Conclusion This study provides a rationale for NT-I7 plus CAR-T cell combination therapy for solid tumors in humans.