tbuckley/cabot-search huggingface dataset:
Extracorporeal membrane oxygenation in the therapy of cardiogenic shock: 1‐year outcomes of the multicentre, randomized <scp>ECMO</scp>‐<scp>CS</scp> trial
Authors: Petr Ostadal, Richard Rokyta, Jiri Karasek, Andreas Kruger, Dagmar Vondrakova, Marek Janotka, Jan Naar, Jana Smalcova, Marketa Hubatova, Milan Hromadka, Stefan Volovar, Miroslava Seyfrydova, Ales Linhart, Jan Belohlavek
Journal: European Journal of Heart Failure (2024)
GNAS knockout potentiates HDAC3 inhibition through viral mimicry-related interferon responses in lymphoma
Authors: Michael Y. He, Kit I. Tong, Ting Liu, Ryder Whittaker Hawkins, Victoria Shelton, Yong Zeng, Mehran Bakhtiari, Yufeng Xiao, Guangrong Zheng, Ali Sakhdari, Lin Yang, Wenxi Xu, David G. Brooks, Rob C. Laister, Housheng Hansen He, Robert Kridel
Journal: Leukemia (2024)

Abstract Despite selective HDAC3 inhibition showing promise in a subset of lymphomas with CREBBP mutations, wild-type tumors generally exhibit resistance. Here, using unbiased genome-wide CRISPR screening, we identify GNAS knockout (KO) as a sensitizer of resistant lymphoma cells to HDAC3 inhibition. Mechanistically, GNAS KO-induced sensitization is independent of the canonical G-protein activities but unexpectedly mediated by viral mimicry-related interferon (IFN) responses, characterized by TBK1 and IRF3 activation, double-stranded RNA formation, and transposable element (TE) expression. GNAS KO additionally synergizes with HDAC3 inhibition to enhance CD8 + T cell-induced cytotoxicity. Moreover, we observe in human lymphoma patients that low GNAS expression is associated with high baseline TE expression and upregulated IFN signaling and shares common disrupted biological activities with GNAS KO in histone modification, mRNA processing, and transcriptional regulation. Collectively, our findings establish an unprecedented link between HDAC3 inhibition and viral mimicry in lymphoma. We suggest low GNAS expression as a potential biomarker that reflects viral mimicry priming for enhanced response to HDAC3 inhibition in the clinical treatment of lymphoma, especially the CREBBP wild-type cases.
Prevalence of steatotic liver disease, advanced fibrosis and cirrhosis among community-dwelling overweight and obese individuals in the USA
Authors: Alexander H Yang, Monica A Tincopa, Federica Tavaglione, Veeral H Ajmera, Lisa M Richards, Maral Amangurbanova, Christian Butcher, Christie Hernandez, Egbert Madamba, Seema Singh, Ricki Bettencourt, Bernd Schnabl, Claude B Sirlin, Rohit Loomba
Journal: Gut (2024)

There are limited prospective data among overweight and obese individuals on the prevalence of advanced fibrosis, and cirrhosis using advanced MRI-based methods in the USA. The aim of this study was to fill that gap in knowledge by prospectively determining the MRI-based prevalence of steatotic liver disease (SLD) and its subcategories, advanced fibrosis and cirrhosis among overweight and obese individuals residing in the USA.
Intravitreal long-term sustained ranibizumab delivery using injectable microgel-embedded hydrogel
Authors: Simin Lee, Jun Young Park, Hye Kyoung Hong, Joo Young Son, Byungwook Kim, Jae Yong Chung, Se Joon Woo, Ki Dong Park
Journal: Asian Journal of Pharmaceutical Sciences (2024)

Retinal vascular disease is the leading cause of visual impairment. Although intravitreal drug injections are the most suitable approach for addressing retinal disorders, existing clinical treatments necessitate repeated administration, imposing a substantial burden on patients with various intraocular complications. This study introduces an injectable and biodegradable hyaluronan microgel (Hm)-embedded gelatin–poly(ethylene glycol)–tyramine hydrogel (HmGh) designed for sustained intravitreal ranibizumab (RBZ) delivery to reduce patient burden and minimize the side effects associated with frequent injections. Hm exhibited a controlled RBZ loading capacity and release profile. HmGh effectively controlled the initial burst release and overall release profile. Cytocompatibility and cellular drug efficacy were also demonstrated. In an animal study, HmGh maintained RBZ concentrations in the vitreous and retina for >120 d. Pharmacokinetic studies showed that the half-life of RBZ-loaded HmGh in the vitreous and retina was 2.55 and 2.05 times longer than that of RBZ-loaded Hm, respectively, and 9.58 and 38.46 times longer than that of RBZ solution, respectively. Importantly, the initial RBZ elimination from HmGh to the aqueous humor was significantly reduced compared to that from the Hm and RBZ solutions. Intraocular degradation and safety were comprehensively evaluated using fundus imaging and histological analyses. In conclusion, this injectable microgel-embedded hydrogel formulation is a promising prolonged drug delivery system for treating various posterior segment eye diseases.
Anti‐Cytokine Active Immunotherapy Based on Supramolecular Peptides for Alleviating IL‐1β‐Mediated Inflammation
Authors: Shamitha Shetty, Yaoying Wu, Christopher Z. Lloyd, Nalini Mehta, Yining Liu, Mia E. Woodruff, Tatiana Segura, Joel H. Collier
Journal: Advanced Healthcare Materials (2024)

Abstract IL‐1β is a principal proinflammatory cytokine underlying multiple local and systemic chronic inflammatory conditions including psoriasis, rheumatoid arthritis, inflammatory bowel disease, and type 2 diabetes. Passive immunotherapies and biologic drugs targeting IL‐1β, while offering significant clinical benefit, nevertheless have limitations such as significant non‐response rates, induction of anti‐drug antibodies, and high costs. Here, an active immunotherapy raising antibody responses against IL‐1β employing self‐assembling peptide nanofibers is described. The nanofibers contain defined quantities of B‐cell epitopes from IL‐1β and exogenous T helper epitopes and employ the Q11 self‐assembling peptide platform. Without adjuvant, the nanofibers raised durable anti‐IL‐1β antibody responses that inhibit IL‐1β activity in vitro and in vivo. In a mouse model of imiquimod‐induced psoriasis, prophylactic immunizations with the nanofibers diminished symptoms of epidermal thickening. This therapeutic effect is associated with biasing the immune response toward an anti‐inflammatory IgG1/Th2 phenotype and a lowered expression of proinflammatory genes in the skin. Further, anti‐IL‐1β nanofibers induced therapeutic immunosuppressive CD62L+ Treg cells. This technology represents a potential alternative for passive immunotherapies and other biologics for treating chronic inflammatory conditions.
Nanoengineered Nonenzymatic Paper‐Based Fluorescent Platform for Pre‐Dilution‐Free and Visual Real‐Time Home Monitoring of Urea for Early Warning of Abnormal Nitrogen‐Based Unhealthy Issues
Authors: Lijuan Chen, Xiaomin Luo, Xuechuan Wang, Yitong Wang, Hao Yang, Suqiu Zhao, Qian Zhang, Xinhua Liu, Huie Jiang
Journal: Advanced Healthcare Materials (2024)

Abstract Distorted urea levels indicate several liver, kidney, or metabolic diseases; however, traditional clinical urea detection relies on urease‐based methods enslaved to well‐known limitations of high‐price, unstable properties, complicated sample pretreatment and analysis procedures, and difficult visual real‐time monitoring. Herein, nonenzymatic paper‐based fluorescent materials (UFP‐BP) are strategically integrated with an on‐demand fluorescent‐sensor (UFP) self‐aggregated nanoparticle on commercial filter paper for pre‐dilution‐free and visual real‐time urea monitoring. The UFP is synthesized and self‐aggregated into the fluorescent nanoparticles for selective urea recognition. Then, the nanoparticles are interstitially loaded on filter paper to nanoengineer the UFP‐BP, achieving selective quantitative urea detection in the normal concentration range (10–1000 m m ). UFP and UFP‐BP can successfully monitor urea levels in real rat urine, artificial simulants, and milk. The proposed sensing platform, integrated with smartphones, offers accurate, quantitative, nonenzymatic, noninvasive, pre‐dilution‐free, on‐site, rapid, low‐cost, easy‐to‐operate, real‐time visual urea detection in food samples and human body fluids. The designed sensing system can provide early warnings of abnormal nitrogen‐based health issues.
Hybrid immunity augments cross-variant protection against COVID-19 among immunocompromised individuals
Authors: Amy May Lin Quek, Suqing Wang, Ooiean Teng, Bhuvaneshwari Shunmuganathan, Bernadette Guek Cheng Er, Nor Fa'izah Binte Mahmud, Isabel Xue Qi Ng, Rashi Gupta, Isabelle Siang Ling Tan, Nikki YJ Tan, Xinlei Qian, Kiren Purushotorman, Hock Luen Teoh, Kay Wei Ping Ng, Yihui Goh, Derek Tuck Loong Soon, Sen Hee Tay, Gim Gee Teng, Margaret Ma, Nisha Suyien Chandran, Juanda Leo Hartono, Paul A. MacAry, Raymond Chee Seong Seet
Journal: Journal of Infection (2024)
Precise Regulation of Reactive Oxygen Species in Tumor Microenvironment for Alleviating Inhibitory Immunogenic Cell Death
Authors: Zichuang Xu, Yuchu He, Xuwu Zhang, Wenkang Tu, Xiaoling Li, Dong Wang, Yaqian Yan, Jiajun Gao, Desong Wang, Dawei Gao
Journal: Advanced Healthcare Materials (2024)

High level of reactive oxygen species (ROS) within the tumor microenvironment (TME) not only damage tumor cells but also diminish the efficacy of immunogenic cell death (ICD) and the activity of tumor-infiltrating T lymphocytes, thereby limiting the effectiveness of immunotherapy. Therefore, precise modulation of ROS level is crucial to effectively eliminate tumor cells and activate ICD-induced immunotherapy. Here, an intelligent yolk shell nanoplatform (SPCCM) that features calcium carbonate shells capable of decomposing under acidic TME conditions, thereby releasing the natural antioxidant proanthocyanidins (PAs) and the photosensitizer Ce6 is designed. PAs scavenge ROS within tumors, extending the survival time of T lymphocytes, while Ce6, as an ICD inducer, generates high ROS concentrations upon laser irradiation, thus reaching the toxic threshold within tumor cells and inducing apoptosis. The resulting apoptotic cells serve as tumor-associated antigens, promoting dendritic cells (DCs) maturation, and activating ICD. By effectively neutralizing ROS in the TME, PAs sustainably reduce ROS level, thereby enhancing DCs activation and restoring antitumor immune cell activity suppressed by ROS (resulting in an eightfold increase in DCs activation). This study demonstrates effective synergistic effects between photodynamic therapy and immunotherapy by precisely modulating ROS level.
PDL1/HER2‐Targeted Lipid‐Encapsulated Oxygen Nanobubbles Combined with Photodynamic Therapy for HER2<sup>+</sup> Breast Cancer Immunotherapy
Authors: Jilai Tian, Shixiao Wan, Zhen Yang, Mengting Wang, Wenzhao Zhou, Guanqun Wo, Shuping Fu, Shiya Zheng, Gaoxin Zhou, Xiaomin Hu, Yichen Guo, Jun Guo
Journal: Advanced Healthcare Materials (2024)

Abstract Programmed death (PD) 1/PD ligand 1 (PDL1) inhibitors are immune checkpoint inhibitors (ICIs) that may facilitate HER2‐positive breast cancer treatment; however, their clinical efficacy remains elusive. Oxygen‐enhanced photodynamic therapy (PDT) increases immunogenic cell death (ICD), providing a promising strategy to render the tumor microenvironment more sensitive to the ICIs. Lipid‐encapsulated oxygen nanobubbles (Lipo‐NBs‐O 2 ) obtained using nanobubbles (NBs) water for oxygen delivery in vivo can facilitate enhanced PDT. Here, dual‐receptor targeted Lipo‐NBs‐O 2 (DRT@Lipo‐NBs‐O 2 ) is prepared by modifying Lipo‐NBs‐O 2 with anti‐PDL1 scFv and the fusion protein anti‐HER2 scFv‐tandem‐repeat cytochrome c (anti‐HER2‐nCyt c ). Copper phthalocyanine is the photosensitizer (PS). DRT@Lipo‐PS‐NBs‐O 2 plus near‐infrared irradiation leads to robust ICD induction, increasing DC activation and CD8 + T‐cell numbers. Modification with anti‐PDL1 scFv improves tumor distribution of DRT@Lipo‐PS‐NBs‐O 2 and plays the ICI role, invigorating CD8 + T cells and boosting the effects of immunotherapy. Oxygen supplied through DRT@Lipo‐PS‐NBs‐O 2 reduces P‐glycoprotein expression. Enhanced PDT and Cyt c can cause tumor cell death, thereby reducing the immune burden. Under dual receptor targeting and laser local irradiation, tumor cells become subject to the combination effects of PDT, ICD, ICIs, and apoptosis; this effectively suppresses tumor growth and metastasis. Lipo‐NBs‐O 2 affords a combination of oxygen delivery and multidrug therapy to alleviate HER2‐positive breast cancer.
Tumor microenvironment immunomodulation by nanoformulated TLR 7/8 agonist and PI3k delta inhibitor enhances therapeutic benefits of radiotherapy
Authors: Mostafa Yazdimamaghani, Oleg V. Kolupaev, Chaemin Lim, Duhyeong Hwang, Sonia J. Laurie, Charles M. Perou, Alexander V. Kabanov, Jonathan S. Serody
Journal: Biomaterials (2024)

Infiltration of immunosuppressive cells into the breast tumor microenvironment (TME) is associated with suppressed effector T cell (Teff) responses, accelerated tumor growth, and poor clinical outcomes. Previous studies from our group and others identified infiltration of immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) as critical contributors to immune dysfunction in the orthotopic claudin-low tumor model, limiting the efficacy of adoptive cellular therapy. However, approaches to target these cells in the TME are currently lacking. To overcome this barrier, polymeric micellular nanoparticles (PMNPs) were used for the co-delivery of small molecule drugs activating Toll-like receptors 7 and 8 (TLR7/8) and inhibiting PI3K delta (PI3Kδ). The immunomodulation of the TME by TLR7/8 agonist and PI3K inhibitor led to type 1 macrophage polarization, decreased MDSC accumulation and selectively decreased tissue-resident Tregs in the TME, while enhancing the T and B cell adaptive immune responses. PMNPs significantly enhanced the anti-tumor activity of local radiation therapy (RT) in mice bearing orthotopic claudin-low tumors compared to RT alone. Taken together, these data demonstrate that RT combined with a nanoformulated immunostimulant diminished the immunosuppressive TME resulting in tumor regression. These findings set the stage for clinical studies of this approach.
Refining the diagnostic utility of OLFM4 in gastric cancer precursors: a call for rigorous methodologies
Authors: Tai Zhang, Xudong Tang
Journal: Molecular Cancer (2024)

This commentary offers a thoughtful discussion of the study by Wei et al. published in the journal on the role of Olfactomedin 4 (OLFM4) in incomplete intestinal metaplasia, a gastric precancerous condition. The original paper introduces OLFM4 as a novel biomarker with potential enhanced diagnostic efficacy compared to established markers. However, several methodological and interpretive considerations are noted. The histopathological findings could be refined by using higher magnification to better elucidate the cellular localization of OLFM4. Including high-resolution images for key stainings would enhance the study's robustness in expression profiling. The statistical approach could be strengthened by employing more rigorous, quantitative methodologies. Additionally, integrating immunofluorescence double-staining may improve the reliability of the results. Discrepancies in immunohistochemical signals across datasets suggest a need for further investigation into tissue section representativeness. Clarifying the term "precancerous lesions of gastric carcinoma cells" to align with widely accepted definitions would enhance clarity. The choice of the GES-1 cell model treated with MNNG could be reconsidered in favor of more established models such as organoids, air-liquid interface models, and gastric cancer-specific cell lines. The in vivo MNNG-alcohol combination model might require additional empirical support, given the limited and conflicting literature on this approach, to ensure an accurate portrayal of IM pathogenesis. The commentary concludes with a call for stringent and standardized methodologies in biomarker research to ensure the clinical applicability and reliability of biomarker studies, particularly in the context of gastric cancer detection and intervention.
656 - Systemic exposure and safety profile of delgocitinib cream in adults with moderate to severe chronic hand eczema in the phase 3 DELTA-2 trial
Authors: Melinda Gooderham, Diamant Thaçi, Tina Damgaard, Daniel Madsen, Anders Soehoel, Robert Bissonnette
Journal: British Journal of Dermatology (2024)

Abstract Introduction/Background In the DELTA-2 (NCT04872101) Phase 3 trial, delgocitinib cream 20 mg/g, a topical pan-Janus kinase inhibitor, was well-tolerated and demonstrated significant improvement in all efficacy endpoints versus cream vehicle in adults with moderate to severe chronic hand eczema (CHE). Objectives The objectives of this analysis were (1) to examine systemic exposure of delgocitinib cream 20 mg/g in adults with moderate to severe CHE in the randomized, double-blind, vehicle-controlled DELTA-2 trial (2) to compare the DELTA-2 systemic exposure with corresponding data following oral administration of delgocitinib in a Phase 1 trial, (3) to present a summary of safety related to delgocitinib cream from the randomized, double-blind, vehicle-controlled DELTA-2 trial. Methods Pharmacokinetic blood sampling in DELTA-2 was performed 2-6 hours after delgocitinib application at Weeks 1, 4, and 16 using a liquid chromatography/mass spectrometry-based method (lower limit of quantitation: 5 pg/ml). In the Phase 1 trial (NCT05050279), single oral doses of delgocitinib were tested in healthy volunteers with sampling performed for up to 24-hours post-administration. Results In DELTA-2, minimal systemic exposure was recorded in 313 delgocitinib-treated patients, with the highest geometric mean plasma concentration being 0.21 ng/ml at Week 1 (n=286). In the Phase 1 trial, the lowest oral delgocitinib dose tested (1.5 mg; n=8) is regarded as subtherapeutic and showed a peak systemic exposure (geometric mean Cmax) of 7.2 ng/ml. In DELTA-2, adverse events (AEs) were reported by 45.7% (n=143/313; delgocitinib cream) and 44.7% (n=71/159; cream vehicle) of patients, with COVID-19 being most common (11.5% vs 12.6%, respectively). The rate of possibly or probably related AEs was low and similar between delgocitinib cream and cream vehicle. No deaths were reported. Few serious AEs were reported with none assessed as related to the study drug. Conclusions The DELTA-2 trial demonstrated minimal systemic exposure in association with a favorable safety profile, supporting a lack of meaningful systemic effect from twice-daily applications of delgocitinib cream in patients with moderate to severe CHE.
630 - Efficacy comparison of targeted systemic monotherapies including lebrikizumab for moderate-to-severe atopic dermatitis: a network meta-analysis
Authors: Jonathan I Silverberg, Thomas Bieber, Amy Paller, Lisa A Beck, Masahiro Kamata, Luis Puig, Marni Wiseman, Khaled Ezzedine, Peter Foley, Erin Johansson, Martin Dossenbach, Bülent Akmaz, Marta Casillas, Andrei Karlsson, Raj Chovatiya
Journal: British Journal of Dermatology (2024)

Abstract Introduction Atopic dermatitis (AD) is a chronic inflammatory skin disease affecting 2–7% of adults globally, with 30% experiencing moderate-to-severe disease. Although several treatments for moderate-to-severe AD are available, the efficacy of many treatments has not been compared in head-to-head trials. Objectives Using a network meta-analysis (NMA), we evaluated the relative efficacy between lebrikizumab, an emerging biologic, and approved targeted systemic treatments for AD. Methods Double-blind, randomized, placebo-controlled clinical trials (systemic monotherapy-only) for moderate-to-severe AD in adults (≥18 years) and adolescents (≥12 years to ≤18 years) published before April 2023 were identified in a systematic literature review. Data were extracted for short-term (12–16 weeks) efficacy outcomes (Investigator’s Global Assessment [IGA] 0/1 with ≥2-point improvement from baseline and the Eczema Area and Severity Index [EASI]) and patient-reported outcomes (Pruritus Numeric Rating Scale [NRS] with ≥4-point improvement from baseline). Bayesian NMAs were performed using random-effects models, with baseline-risk adjustment. Key estimates from the NMAs included pairwise differences between all treatments and absolute response rates for each treatment. Results Twenty-two clinical trials were included. For % achieving IGA 0/1, at 12–16 weeks, the estimated response rates (posterior median and 95% credible interval) for each of the treatments were: upadacitinib 30 mg 55.8% (43.7–64.2%), upadacitinib 15 mg 41.3% (30.1–50.0%), abrocitinib 200 mg 39.0% (29.8–47.8%), dupilumab 300 mg 31.8% (23.1–38.7%), lebrikizumab 250 mg 31.4% (24.1–39.2%), abrocitinib 100 mg 24.5% (17.5–32.0%), tralokinumab 300 mg 17.3% (12.8–22.2%), baricitinib 4 mg 16.7% (9.8–25.5%), baricitinib 2 mg 15.5% (9.6–22.0%), and placebo 6.0% (4.3–7.3%). Similar trends were observed for the EASI and pruritus NRS responses at 12–16 weeks. Conclusions This 16-week NMA shows that lebrikizumab had a similar response rate to dupilumab, the most widely used targeted systemic therapy for AD, and may represent a valuable treatment option for moderate-to-severe AD.
648 - Response to ritlecitinib with or without narrow band ultraviolet B (nbUVB) add-on therapy in patients with active non-segmental vitiligo (NSV)
Authors: Yuji Yamaguchi, Elena Peeva, Roni Adiri, Pranab Ghosh, Lynne Napatalung, Iltefat Hamzavi, Amit G Pandya, Ronald N Shore, Khaled Ezzedine, Emma Guttman-Yassky
Journal: British Journal of Dermatology (2024)

Abstract Introduction/Background Ritlecitinib, a JAK3/TEC family kinase inhibitor, demonstrated efficacy in a Phase 2b trial of patients with NSV. Objectives To evaluate the efficacy and tolerability of ritlecitinib with or without nbUVB add-on therapy in patients with NSV. Methods In a Phase 2b trial, following a 24-week placebo-controlled dose-ranging period, patients with NSV received ritlecitinib 200 mg for 4 weeks then 50 mg for 20 weeks, with or without nbUVB phototherapy 2x/week. Missing data were handled using observed case (OC) and last observation carried forward (LOCF). Results 43 and 187 patients received ritlecitinib+nbUVB and ritlecitinib-monotherapy, respectively. Nine patients receiving ritlecitinib+nbUVB discontinued due to nbUVB group-specific efficacy criteria requiring &amp;gt;10% improvement in %change from baseline (CFB) in Total-Vitiligo Area Scoring Index (T-VASI) at Week 12. At Week 24, mean (90% CI) %CFB in Facial-VASI (F-VASI) was -69.6 (-79.1, -60.1) vs -55.1 (-59.4, -50.7) (OC; P=0.009) and -57.0 (-65.3, -48.7) vs -51.5 (-55.9, -47.1) (LOCF; P=0.158), for ritlecitinib+nbUVB vs ritlecitinib-monotherapy, respectively. 60.9% (43.1%, 77.2%) vs 29.2% (22.8%, 35.9%) (OC; P=0.007) and 44.4% (30.2%, 59.1%) vs 27.4% (21.7%, 33.4%) (LOCF; P=0.081) of patients, respectively, achieved ≥75% improvement in F-VASI. Mean (90% CI) %CFB in T-VASI at Week 24 was -46.8 (-54.5, -39.2) vs -24.5 (-28.1, -21.0) (OC; P&amp;lt;0.001) and -29.4 (-36.5, -22.2) vs -21.2 (-25.0, -17.4) (LOCF; P=0.043) for ritlecitinib+nbUVB vs ritlecitinib-monotherapy, respectively. 50.0% (33.3%, 66.7%) vs 15.2% (11.1%, 20.3%) (OC; P&amp;lt;0.001) and 32.6% (22.1%, 44.7%) vs 14.4% (10.6%, 19.0%) (LOCF, P=0.014) of patients, respectively, achieved ≥50% improvement in T-VASI. nbUVB addition to ritlecitinib was well-tolerated with no new safety signals. Conclusions Ritlecitinib alone and with nbUVB therapy improved facial and total body repigmentation and was well-tolerated. nbUVB may improve ritlecitinib efficacy.