tbuckley/cabot-search huggingface dataset:
Smad1/5 is acetylated in the dorsal aortae of the mouse embryo before the onset of blood flow, driving early arterial gene expression
Authors: Margo Daems, Ljuba C Ponomarev, Rita Simoes-Faria, Max Nobis, Colinda L G J Scheele, Aernout Luttun, Bart Ghesquière, An Zwijsen, Elizabeth A V Jones
Journal: Cardiovascular Research (2024)

Abstract Aims During embryonic development, arteriovenous (AV) differentiation ensures proper blood vessel formation and maturation. Defects in arterial or venous identity cause inappropriate fusion of vessels, resulting in atypical shunts, so-called AV malformations (AVMs). Currently, the mechanism behind AVM formation remains unclear, and treatment options are fairly limited. Mammalian AV differentiation is initiated before the onset of blood flow in the embryo; however, this pre-flow mechanism is poorly understood. Here, we aimed to unravel the role of Smad1/5 signalling in pre-flow arterial identity and, in the process, uncovered an unexpected control mechanism of Smad1/5 signalling. Methods and results We establish that despite Notch1 being expressed in the pre-flow mouse embryo, it is not activated, nor is it necessary for the expression of the earliest arterial genes in the dorsal aortae (i.e. Hey1 and Gja4). Furthermore, interrupting blood flow by using the Ncx1 KO model completely prevents the activation of Notch1 signalling, suggesting a strong role of shear stress in maintaining arterial identity. We demonstrate that early expression of Hey1 and Gja4 requires SMAD1/5 signalling. Using embryo cultures, we show that Smad1/5 signalling is activated through the Alk1/Alk5/transforming growth factor (TGF)βR2 receptor complex, with TGFβ1 as a necessary ligand. Furthermore, our findings demonstrate that early arterial gene expression requires the acetylation of Smad1/5 proteins, rendering them more sensitive to TGFβ1 stimulation. Blocking acetyl-CoA production prevents pre-flow arterial expression of Hey1 and Gja4, while stabilizing acetylation rescues their expression. Conclusion Our findings highlight the importance of the acetyl-CoA production in the cell and provide a novel control mechanism of Smad1/5 signalling involving protein acetylation. As disturbed canonical Smad1/5 signalling is involved in several vascular conditions, our results offer new insights in treatment options for circumventing canonical Smad1/5 signalling.
British Association of Dermatologists and British Society for Rheumatology living guideline for managing people with Behçets 2024
Authors: Ruth Murphy, Robert J Moots, Paul Brogan, Aykut F Çelik, Mark Clement-Jones, Ian Coulson, Adam P Croft, Suzanne Crozier, Laura Forrest, Jonathan Harrold, Steve Higgins, Ali S M Jawad, Seema Kalra, Sidra S Khan, Hilary McKee, Clare E Pain, Harry Petrushkin, Ana Poveda-Gallego, Jane Setterfield, Poonam Sharma, Richard West, Christina Wlodek, Maria Hashme, Lina Manounah, M Firouz Mohd Mustapa, Alina M Constantin
Journal: British Journal of Dermatology (2024)

The overall objective of the guideline is to provide up-to-date, evidence-based recommendations for the management of Behçets. The document aims to offer an appraisal of all relevant literature up to 25 August 2023 focusing on any key developments; to address important, practical clinical questions relating to the primary guideline objective; and to provide guideline recommendations and appropriate research recommendations.
Inhaled colistimethate sodium in patients with bronchiectasis and Pseudomonas aeruginosa infection: results of PROMIS-I and PROMIS-II, two randomised, double-blind, placebo-controlled phase 3 trials assessing safety and efficacy over 12 months
Authors: Charles S Haworth, Michal Shteinberg, Kevin Winthrop, Alan Barker, Francesco Blasi, Katerina Dimakou, Lucy C Morgan, Anne E O'Donnell, Felix C Ringshausen, Oriol Sibila, Rachel M Thomson, Kevin J Carroll, Federica Pontenani, Paola Castellani, James D Chalmers
Journal: The Lancet Respiratory Medicine (2024)
MK-5475, an inhaled soluble guanylate cyclase stimulator, for treatment of pulmonary arterial hypertension: the INSIGNIA-PAH study
Authors: Marc Humbert, Paul M Hassoun, Kelly M Chin, Guillermo Bortman, Mahesh J Patel, Carmen La Rosa, Wei Fu, Maria José Loureiro, Marius M Hoeper
Journal: European Respiratory Journal (2024)

Background MK-5475 is an investigational inhaled soluble guanylate cyclase stimulator hypothesised to avoid most side-effects of systemic vasodilation. Methods The phase 2 INSIGNIA-PAH ( NCT04732221 ) trial randomised adults with pulmonary arterial hypertension (PAH) on stable background therapy 1:1:1:1 to once-daily dosing with placebo, MK-5475 32 µg, 100 µg or 380 µg via dry powder inhalation for 12 weeks. Objectives The objectives were to evaluate pulmonary vascular resistance (PVR; primary), 6-min walk distance (6MWD; secondary), additional selected haemodynamic parameters, and safety and tolerability in participants with PAH. Results 168 participants were randomised to placebo (n=41), MK-5475 32 µg (n=42), 100 µg (n=44), and 380 µg (n=41). Median age was 51 years. Most participants were female (73.8%), diagnosed with idiopathic PAH (63.7%), receiving concomitant phosphodiesterase type 5 inhibitors (PDE5i; 93.5%), and treated with double or triple combination therapy (85.1%). At week 12, the placebo-corrected changes in PVR by least-squares means were −9.2% (95% CI −21.3%, 2.9%; p=0.068) with 32 µg, −22.0% (95% CI −33.7%, −10.3%; p&lt;0.001) with 100 µg, and −19.9% (95% CI −33.4%, −6.4%; p=0.002) with 380 µg MK-5475. No treatment differences versus placebo were observed in 6MWD. Treatment-related adverse events and serious adverse events were similar across treatment groups. Three participants died: two on placebo and one on MK-5475 100 µg. One participant had symptomatic hypotension and one had haemoptysis (both on MK-5475 100 µg). Conclusions In participants with PAH on stable background therapy, including PDE5i, inhaled MK-5475 reduced PVR and was well tolerated, without evidence of systemic side-effects such as hypotension, suggesting a pulmonary selective pharmacodynamic effect.
Cathepsin C (dipeptidyl peptidase 1) inhibition in adults with bronchiectasis: AIRLEAF®, a Phase II randomised, double-blind, placebo-controlled, dose-finding study
Authors: James D Chalmers, Michal Shteinberg, Marcus A Mall, Anne E O'Donnell, Henrik Watz, Abhya Gupta, Edith Frahm, Anastasia Eleftheraki, Johanna Rauch, Sanjay H Chotirmall, April W Armstrong, Peter Eickholz, Naoki Hasegawa, Wiebke Sauter, Pamela J McShane
Journal: European Respiratory Journal (2024)

Bronchiectasis is characterised by uncontrolled neutrophil serine protease (NSP) activity. Cathepsin C (CatC; dipeptidyl peptidase 1) activates NSPs during neutrophil maturation. CatC inhibitors can potentially reduce neutrophil-mediated lung damage. This Phase II, randomised, double-blind, placebo-controlled trial (AIRLEAF®; NCT05238675 ) evaluated efficacy, safety and optimal dosing of BI 1291583, a novel, reversible CatC inhibitor, in adults with bronchiectasis. In total, 322 participants were randomised (2:1:1:2) to receive one of three oral doses of BI 1291583 (1 mg/2.5 mg/5 mg) or placebo for 24 to 48 weeks. A multiple comparison procedure and modelling approach was used to demonstrate a non-flat dose–response curve based on the time to first pulmonary exacerbation up to Week 48. In addition, efficacy of individual BI 1291583 doses was evaluated based on the frequency of exacerbations, severe exacerbations (fatal or leading to hospitalisation and/or intravenous antibiotic administration), lung function and quality of life. A significant dose-dependent benefit of BI 1291583 over placebo was established based on time to first exacerbation (shape: Emax; adjusted p-value: 0.0448). Treatment with BI 1291583 5 mg and 2.5 mg numerically reduced the risk of an exacerbation compared with placebo (hazard ratios: 0.71 and 0.66, 95% CIs 0.48–1.05 and 0.40–1.08; both p&gt;0.05). BI 1291583 2.5 mg showed numerically better efficacy compared with 5 mg across several endpoints; 1 mg was similar to placebo. The safety profile of BI 1291583 was similar to placebo. Treatment with BI 1291583 resulted in a reduction in the risk of experiencing an exacerbation in adults with bronchiectasis.
Variants in tubule epithelial regulatory elements mediate most heritable differences in human kidney function
Authors: Gabriel B Loeb, Pooja Kathail, Richard W Shuai, Ryan Chung, Reinier J Grona, Sailaja Peddada, Volkan Sevim, Scot Federman, Karl Mader, Audrey Y Chu, Jonathan Davitte, Juan Du, Alexander R Gupta, Chun Jimmie Ye, Shawn Shafer, Laralynne Przybyla, Radu Rapiteanu, Nilah M Ioannidis, Jeremy F Reiter
Journal: Nature Genetics (2024)
VEGF-A-mediated venous endothelial cell proliferation results in neoangiogenesis during neuroinflammation
Authors: Sanjid Shahriar, Saptarshi Biswas, Kaitao Zhao, Uğur Akcan, Mary Claire Tuohy, Michael D Glendinning, Ali Kurt, Charlotte R Wayne, Grace Prochilo, Maxwell Z Price, Heidi Stuhlmann, Rolf A Brekken, Vilas Menon, Dritan Agalliu
Journal: Nature Neuroscience (2024)
Evaluation and Management of Kidney Dysfunction in Advanced Heart Failure: A Scientific Statement From the American Heart Association
Authors: W.H. Wilson Tang, Marie A. Bakitas, Xingxing S. Cheng, James C. Fang, Savitri E. Fedson, Amy G. Fiedler, Pieter Martens, Wendy I. McCallum, Modele O. Ogunniyi, Janani Rangaswami, Nisha Bansal
Journal: Circulation (2024)

Early identification of kidney dysfunction in patients with advanced heart failure is crucial for timely interventions. In addition to elevations in serum creatinine, kidney dysfunction encompasses inadequate maintenance of sodium and volume homeostasis, retention of uremic solutes, and disrupted endocrine functions. Hemodynamic derangements and maladaptive neurohormonal upregulations contribute to fluctuations in kidney indices and electrolytes that may recover with guideline-directed medical therapy. Quantifying the extent of underlying irreversible intrinsic kidney disease is crucial in predicting whether optimization of congestion and guideline-directed medical therapy can stabilize kidney function. This scientific statement focuses on clinical management of patients experiencing kidney dysfunction through the trajectory of advanced heart failure, with specific focus on (1) the conceptual framework for appropriate evaluation of kidney dysfunction within the context of clinical trajectories in advanced heart failure, including in the consideration of advanced heart failure therapies; (2) preoperative, perioperative, and postoperative approaches to evaluation and management of kidney disease for advanced surgical therapies (durable left ventricular assist device/heart transplantation) and kidney replacement therapies; and (3) the key concepts in palliative care and decision-making processes unique to individuals with concomitant advanced heart failure and kidney disease.
Management of cardiogenic shock: state-of-the-art
Authors: Christian Jung, Raphael Romano Bruno, Marwan Jumean, Susanna Price, Konstantin A Krychtiuk, Kollengode Ramanathan, Josef Dankiewicz, John French, Clement Delmas, Alexandra-Arias Mendoza, Holger Thiele, Sabri Soussi
Journal: Intensive Care Medicine (2024)
Effect of an exercise intervention or combined exercise and diet intervention on health-related quality of life-physical functioning after kidney transplantation: the Active Care after Transplantation (ACT) multicentre randomised controlled trial
Authors: Tim J Knobbe, Daan Kremer, Dorien M Zelle, Gerald Klaassen, Desie Dijkema, Iris M Y van Vliet, Paul B Leurs, Frederike J Bemelman, Maarten H L Christiaans, Stefan P Berger, Gerjan Navis, Stephan J L Bakker, Eva Corpeleijn
Journal: The Lancet Healthy Longevity (2024)
Half-Life and Clearance of Cardiac Troponin I and Troponin T in Humans
Authors: Jonas Henrik Kristensen, Rasmus Bo Hasselbalch, Nina Strandkjær, Nicoline Jørgensen, Morten Østergaard, Peter Hasse Møller-Sørensen, Jens Christian Nilsson, Shoaib Afzal, Pia Rørbæk Kamstrup, Morten Dahl, Mustafa Vakur Bor, Ruth Frikke-Schmidt, Niklas Rye Jørgensen, Line Rode, Lene Holmvang, Jesper Kjærgaard, Lia Evi Bang, Julie Forman, Kim Dalhoff, Allan S. Jaffe, Kristian Thygesen, Henning Bundgaard, Kasper Karmark Iversen
Journal: Circulation (2024)

BACKGROUND: Cardiac troponin (cTn) is key in diagnosing myocardial infarction (MI). After MI, the clinically observed half-life of cTn has been reported to be 7 to 20 hours, but this estimate reflects the combined elimination and simultaneous release of cTn from cardiomyocytes. More precise timing of myocardial injuries necessitates separation of these 2 components. We used a novel method for determination of isolated cTn elimination kinetics in humans. METHODS: Patients with MI were included within 24 hours after revascularization and underwent plasmapheresis to obtain plasma with a high cTn concentration. After at least 3 weeks, patients returned for an autologous plasma retransfusion followed by blood sampling for 8 hours. cTn was measured with 5 different high-sensitivity cTn assays. RESULTS: Of 25 included patients, 20 participants (mean age, 64.5 years; SD, 8.2 years; 4 women [20%]) received a retransfusion after a median of 5.8 weeks (interquartile range, 5.0–6.9 weeks) after MI. After retransfusion of a median of 620 mL (range, 180–679 mL) autologous plasma, the concentration of cTn in participants’ blood increased 4 to 445 times above the upper reference level of the 5 high-sensitivity cTn assays. The median elimination half-life ranged from 134.1 minutes (95% CI, 117.8–168.0) for the Elecsys high-sensitivity cTnT assay to 239.7 minutes (95% CI, 153.7–295.1) for the Vitros high-sensitivity cTnI assay. The median clearance of cTnI ranged from 40.3 mL/min (95% CI, 32.0–44.9) to 52.7 mL/min (95% CI, 42.2–57.8). The clearance of cTnT was 77.0 mL/min (95% CI, 45.2–95.0). CONCLUSIONS: This novel method showed that the elimination half-life of cTnI and cTnT was 5 to 16 hours shorter than previously reported. This indicates a considerably longer duration of cardiomyocyte cTn release after MI than previously thought. Improved knowledge of timing of myocardial injury may call for changes in the management of MI and other disorders with myocardial injury.
Legumain‐Guided Ferulate‐Peptide Self‐Assembly Enhances Macrophage‐Endotheliocyte Partnership to Promote Therapeutic Angiogenesis After Myocardial Infarction
Authors: Delong Xu, Shenghui Bi, Jiejing Li, Shaodan Ma, Ze‐an Yu, Yenan Wang, Huiming Chen, Jie Zhan, Xudong Song, Yanbin Cai
Journal: Advanced Healthcare Materials (2024)

Abstract Promoting angiogenesis and modulating the inflammatory microenvironment are promising strategies for treating acute myocardial infarction (MI). Macrophages are crucial in regulating inflammation and influencing angiogenesis through interactions with endothelial cells. However, current therapies lack a comprehensive assessment of pathological and physiological subtleties, resulting in limited myocardial recovery. In this study, legumain‐guided ferulate‐peptide nanofibers (LFPN) are developed to facilitate the interaction between macrophages and endothelial cells in the MI lesion and modulate their functions. LFPN exhibits enhanced ferulic acid (FA) aggregation and release, promoting angiogenesis and alleviating inflammation. The multifunctional role of LFPN is validated in cells and an MI mouse model, where it modulated macrophage polarization, attenuated inflammatory responses, and induces endothelial cell neovascularization compare to FA alone. LFPN supports the preservation of border zone cardiomyocytes by regulating inflammatory infiltration in the ischemic core, leading to significant functional recovery of the left ventricle. These findings suggest that synergistic therapy exploiting multicellular interaction and enzyme guidance may enhance the clinical translation potential of smart‐responsive drug delivery systems to treat MI. This work emphasizes macrophage‐endothelial cell partnerships as a novel paradigm to enhance cell interactions, control inflammation, and promote therapeutic angiogenesis.
Development of Neural Cells and Spontaneous Neural Activities in Engineered Brain‐Like Constructs for Transplantation
Authors: Ke Gai, Mengliu Yang, Wei Chen, Chenyujun Hu, Xiao Luo, Austin Smith, Caizhe Xu, Hefeng Zhang, Xiang Li, Wei Shi, Wei Sun, Feng Lin, Yu Song
Journal: Advanced Healthcare Materials (2024)

Abstract Stem cell transplantation has demonstrated efficacy in treating neurological disorders by generating functional cells and secreting beneficial factors. However, challenges remain for current cell suspension injection therapy, including uncontrollable cell distribution, the potential for tumor formation, and limited ability to treat spatial defects. Therefore, implants with programmable cell development, tailored 3D structure, and functionalized biomaterials have the potential to both control cell distribution and reduce or heal spatial defects. Here, a biomimetic material system comprising gelatin, alginate, and fibrinogen has been developed for neural progenitor cell constructs using 3D printing. The resulting constructs exhibit excellent formability, stability, and developmental functions in vitro, as well as biocompatibility and integration into the hippocampus in vivo. The controllability, reproducibility, and material composition of the constructs show potential for use in personalized stem cell‐based therapies for defective neurological disorders, neural development research, disease modeling, and organoid‐derived intelligent systems.
Extracellular Vesicles-Hitchhiking Boosts the Deep Penetration of Drugs to Amplify Anti-Tumor Efficacy
Authors: Min Gao, Qiuting Sun, Ruijie Zhang, Guisong Shan, Huiru Zhang, Rui Peng, Mengyu Liu, Gengyun Sun, Lei Qiao, Yang Li, Xiaoyan He
Journal: Biomaterials (2024)
Non-invasive assessment of severe liver fibrosis in patients with Fontan-associated liver disease: The VALDIG-EASL FONLIVER cohort
Authors: Luis Téllez, Diego Rincón, Audrey Payancé, Anaïs Jaillais, Pascal Lebray, Enrique Rodríguez de Santiago, Ana Clemente, Valerie Paradis, Bruno Lefort, Elvira Garrido-Lestache, Raquel Prieto, Laurence Iserin, Matthias Tallegas, Elena Garrido, María Torres, Alfonso Muriel, Cristian Perna, María Jesús Del Cerro, Louis d'Alteroche, Pierre-Emmanuel Rautou, Rafael Bañares, Agustín Albillos
Journal: Journal of Hepatology (2024)
Targeting PYK2 with heterobifunctional T6BP helps mitigate MASLD and MASH-HCC progression
Authors: Minxuan Xu, Junjie Zhao, Liancai Zhu, Chenxu Ge, Yan Sun, Ranran Wang, Yuanyuan Li, Xianling Dai, Qin Kuang, Linfeng Hu, Jing Luo, Gang Kuang, Yanrong Ren, Bochu Wang, Jun Tan, Shengbin Shi
Journal: Journal of Hepatology (2024)
Targeting Rap1b signaling cascades with CDNF: Modulating Platelet Activation, Regulating Plasma Oxylipins and Mitigating Reperfusion Injury in stroke
Authors: Jui-Sheng Wu, Helike Lõhelaid, Chih-Chin Shih, Hock-Kean Liew, Vicki Wang, Wei-Fen Hu, Yuan-Hao Chen, Mart Saarma, Mikko Airavaara, Kuan-Yin Tseng
Journal: Molecular Therapy (2024)
Microbiota-induced S100A11-RAGE axis underlies immune evasion in right-sided colon adenomas and is a therapeutic target to boost anti-PD1 efficacy
Authors: Qiming Zhou, Linhan Lei, Junhong Cheng, Junyou Chen, Yuyang Du, Xuehua Zhang, Qing Li, Chuangen Li, Haijun Deng, Chi Chun Wong, Baoxiong Zhuang, Guoxin Li, Xiaowu Bai
Journal: Gut (2024)

Background Tumourigenesis in right-sided and left-sided colons demonstrated distinct features. Objective We aimed to characterise the differences between the left-sided and right-sided adenomas (ADs) representing the early stage of colonic tumourigenesis. Design Single-cell and spatial transcriptomic datasets were analysed to reveal alterations between right-sided and left-sided colon ADs. Cells, animal experiments and clinical specimens were used to verify the results. Results Single-cell analysis revealed that in right-sided ADs, there was a significant reduction of goblet cells, and these goblet cells were dysfunctional with attenuated mucin biosynthesis and defective antigen presentation. An impairment of the mucus barrier led to biofilm formation in crypts and subsequent bacteria invasion into right-sided ADs. The regions spatially surrounding the crypts with biofilm occupation underwent an inflammatory response by lipopolysaccharide (LPS) and an apoptosis process, as revealed by spatial transcriptomics. A distinct S100A11 + epithelial cell population in the right-sided ADs was identified, and its expression level was induced by bacterial LPS and peptidoglycan. S100A11 expression facilitated tumour growth in syngeneic immunocompetent mice with increased myeloid-derived suppressor cells (MDSC) but reduced cytotoxic CD8+ T cells. Targeting S100A11 with well-tolerated antagonists of its receptor for advanced glycation end product (RAGE) (Azeliragon) significantly impaired tumour growth and MDSC infiltration, thereby boosting the efficacy of anti-programmed cell death protein 1 therapy in colon cancer. Conclusion Our findings unravelled that dysfunctional goblet cells and consequential bacterial translocation activated the S100A11-RAGE axis in right-sided colon ADs, which recruits MDSCs to promote immune evasion. Targeting this axis by Azeliragon improves the efficacy of immunotherapy in colon cancer.
Racial and socioeconomic disparities in NSCLC molecular diagnostics uptake
Authors: Stephanie Tuminello, Wiley M Turner, Matthew Untalan, Tara Ivic-Pavlicic, Raja Flores, Emanuela Taioli
Journal: JNCI Journal of the National Cancer Institute (2024)

Abstract Background Precision therapies, such as targeted and immunotherapies, have substantially changed the landscape of late-stage non-small cell lung cancer (NSCLC). Yet utilization of these therapies is disproportionate across strata defined by race and socioeconomic status (SES), possibly due to disparities in molecular diagnostic testing (or “biomarker testing”), which is a prerequisite to treatment. Methods We extracted a cohort of NSCLC patients from the Surveillance, Epidemiology and End Results (SEER)-Medicare linked data. The primary outcome was receipt of a molecular diagnostic test, based on claims data. The primary predictors were race and SES. Likelihood of receiving a molecular diagnostic test, and overall survival (OS), were investigated using logistic and Cox proportional hazards regression, adjusted for sex, age, residence, histology, marital status, and comorbidity. Results Of the 28,511 NSCLC patients, 11,209 (39.3%) received molecular diagnostic testing. Compared to White patients, fewer Black patients received a molecular diagnostic test (40.4% vs 27.9%; p &amp;lt; .001). After adjustment, Black patients (ORadj [odds ratio]: 0.64; 95% CI [confidence interval]: 0.58-0.71) and those living in areas with greater poverty (ORadj: 0.85; 95% CI: 0.80-0.89) had statistically significant decreased likelihood of molecular diagnostic testing. Patients who did receive testing had a statistically significant decreased risk of death (HRadj [hazards ratio]: 0.74; 95% CI: 0.72-0.76). These results held in the stratified analysis of stage IV NSCLC patients. Conclusion Disparities exist in comprehensive molecular diagnostics, which is critical for clinical decision making. Addressing barriers to molecular testing could help close gaps in cancer care and improve patient outcomes.