tbuckley/cabot-search huggingface dataset:
Development of an open-source tool for risk assessment in pulmonary endarterectomy
Authors: James Liley, Katherine Bunclark, Michael Newnham, John Cannon, Karen Sheares, Dolores Taboada, Choo Ng, Nicholas Screaton, David Jenkins, Joanna Pepke-Zaba, Mark Toshner
Journal: European Respiratory Journal (2024)

Background Risk prediction tools are routinely utilised in cardiothoracic surgery but have not been developed for pulmonary endarterectomy (PEA). There is no data on whether patients undergoing PEA may benefit from a tailored risk modelling approach. We develop and validate a clinically-usable tool to predict PEA 90-day mortality (90 DM) with the secondary aim of informing factors that may influence five-year mortality (5 YM) and improvement in patient-reported outcomes (PROchange) using common clinical assessment parameters. Derived model predictions were compared to those of the currently most widely implemented cardiothoracic surgery risk tool, EuroSCORE II. Methods Consecutive patients undergoing PEA for chronic thromboembolic pulmonary hypertension (CTEPH) between 2007 and 2018 (n=1334) were included in a discovery dataset. Outcome predictors included an intentionally broad array of variables, incorporating demographic, functional and physiological measures. Three statistical models (linear regression, penalised linear regression and random forest) were considered per outcome, each calibrated, fitted and assessed using cross-validation, ensuring internal consistency. The best predictive models were incorporated into an open-source PEA risk tool and validated using a separate prospective PEA cohort from 2019 to 2021 (n=443) at the same institution. Results Random forest models had the greatest predictive accuracy for all three outcomes. Novel risk models had acceptable discriminatory ability for outcome 90 DM (AUROC 0.82) outperforming that of EuroSCORE II (AUROC 0.65). CTEPH related factors were important for outcome 90 DM but 5 YM was driven by non-CTEPH factors, dominated by generic cardiovascular risk. We were unable to accurately predict a positive improvement in PRO status (AUROC 0.47). Conclusions Operative mortality from PEA can be predicted pre-operatively to a potentially clinically useful degree. Our validated models enable individualised risk stratification at clinician point-of-care to better inform shared decision making.
Defining adherence phenotype and endotypes to personalise asthma management
Authors: Amy Hai Yan Chan, Heather Hoch De Keyser, Rob Horne, Stanley J. Szefler
Journal: European Respiratory Journal (2024)

<title>Extract</title> The Lancet Commission "After asthma: redefining airways diseases" called for greater emphasis on treatable traits that are quantifiable and modifiable, advocating for a precision medicine approach [1]. Currently, precision medicine focuses on biological and physiological markers. These markers give information on the "what", <italic>e.g.</italic> disease control, but do not give insights into the "why", <italic>e.g.</italic> the reasons driving poor asthma control. In this Viewpoint, we discuss expanding this idea of precision medicine to adherence [2].
Update on cancer screening in children with syndromes of bone lesions, hereditary leiomyoma and renal cell carcinoma syndrome, and other rare syndromes
Authors: Orli Michaeli, Sun Young Kim, Sarah G. Mitchell, Marjolijn C.J. Jongmans, Jonathan D. Wasserman, Melissa R. Perrino, Anirban Das, Suzanne P. MacFarland, Sarah R. Scollon, Mary-Louise C. Greer, Nara Sobreira, Bailey Gallinger, Philip J. Lupo, David Malkin, Kami Wolfe Schneider, Kris Ann P. Schultz, William D. Foulkes, Emma R. Woodward, Douglas R. Stewart
Journal: Clinical Cancer Research (2024)

Abstract The management of children with syndromes associated with an increased risk of benign and malignant neoplasms is a complex challenge for health care professionals. The 2023 American Association for Cancer Research Childhood Cancer Predisposition Workshop provided updated consensus guidelines on cancer surveillance in these syndromes, aiming to improve early detection and intervention and reduce morbidity associated with such neoplasms. In this article, we review several of the rare conditions discussed in this workshop. Ollier disease and Maffucci syndrome are enchondromatoses (disorders featuring benign bone lesions) with up to 50% risk of malignancy, including chondrosarcoma. These patients require surveillance with baseline whole-body MRI and routine monitoring of potential malignant transformation of bony lesions. Hereditary multiple osteochondromas carry a lower risk of chondrosarcoma (&amp;lt;6%) but still require lifelong surveillance and baseline imaging. Related syndromes of benign bone lesions are also described. Hereditary leiomyomatosis and renal cell carcinoma syndrome, associated with fumarate hydratase pathogenic variants, is discussed in detail. Surveillance for renal cell carcinoma in pediatric age is recommended, as well as prompt intervention when a lesion is detected. Schinzel–Giedion syndrome and Rubinstein–Taybi syndrome are described for their associated malignancies and other complications, as well as expert consensus on the need for childhood cancer surveillance. Clinical recommendations, including imaging modalities and frequency of screenings, are proposed and are tailored to each syndrome's age-specific tumor risk profile. In all syndromes, patients and their families should be educated about the potential malignancy risk and advised to seek medical care for rapid growth of a mass, persistent pain, or other unexplained symptoms.
Cardiovascular Benefits and Safety Profile of Macrolide Maintenance Therapy in Patients with Bronchiectasis
Authors: Ran Guo, Dennis Wat, Steven Ho Man Lam, Tommaso Bucci, Christopher Tze-Wei Tsang, An-Ping Cai, Yap-Hang Chan, Qing-Wen Ren, Jia-Yi Huang, Jing-Nan Zhang, Wen-Li Gu, Ching-Yan Zhu, Yik-Ming Hung, Freddy Frost, Gregory Y H Lip, Kai-Hang Yiu
Journal: European Respiratory Journal (2024)

Background Macrolide maintenance therapy (MMT) has demonstrated notable efficacy in reducing exacerbation in patients with bronchiectasis, which is a major risk factor for cardiovascular events. However, a comprehensive assessment of the cardiovascular benefits and safety profile of MMT in this population is lacking. Methods This territory-wide cohort study analyzed patients diagnosed with bronchiectasis in Hong Kong between 2001 and 2018. Patients were classified as MMT receivers or macrolide non-receivers based on the administration of MMT. Propensity score (PS) matching was employed for confounding factors adjustment. The primary outcome of interest was major adverse cardiovascular events (MACE), a composite of cardiovascular death, myocardial infarction and stroke. The safety outcome was the occurrence of ventricular arrhythmias or sudden cardiac death. Cox proportional hazard regression analysis was utilized to compare the incidence of outcomes across the two groups. Results A total of 22 895 patients with bronchiectasis were identified. Following 1:2 PS matching, the final cohort consisted of 3137 individuals, with 1123 MMT receivers and 2014 macrolide non-receivers. MMT administration was associated with a significant reduced risk of MACE (16.38 versus 24.11 events per 1000 person years; HR 0.68; 95% CI 0.52–0.90). Importantly, the use of MMT was not associated with elevated risk of ventricular arrhythmias or sudden cardiac death (7.17 versus 7.67 events per 1000 person years; HR 0.93; 95% CI 0.60–1.44). Conclusions The administration of MMT in patients with bronchiectasis was associated with a significant reduction in the risk of MACE, without any evidence suggesting an increased risk of severe arrhythmia-related adverse events.
Outpatient Management of Cancer-Associated Pulmonary Embolism: A Systematic Review and Meta-Analysis
Authors: Aurélien Delluc, Michelle Pradier, Deborah M. Siegal, Grégoire Le Gal, Marc Carrier, Tzu-Fei Wang
Journal: European Respiratory Journal (2024)

Introduction Outpatient management of pulmonary embolism (PE) remains controversial in patients with cancer due to their higher risks of mortality, recurrent venous thromboembolism (VTE) and bleeding complications. This systematic review and meta-analysis aimed to evaluate the safety and feasibility of outpatient management of cancer-associated PE. Methods We searched MEDLINE, Embase, Cochrane Central, and Scopus databases from inception to May 30, 2024, for studies on outpatient management of cancer-associated PE. Eligible studies included randomized controlled trials, cohort studies, and case-control studies with ≥10 patients. The primary outcome was 30-day-all-cause mortality; secondary outcomes included VTE-related mortality, major bleeding and recurrent VTE at 30 days. Meta-analysis was performed using random effects models, and heterogeneity was assessed with the I 2 statistic. Results Nineteen studies (13 full-article, 6 abstract-only) with a total of 1589 patients managed as outpatients were identified. Criteria for outpatient management of cancer-associated PE were reported in 14 studies. The pooled 30-day all-cause mortality rate was 1.74% (95% CI: 0.99–3.03; I 2 =0%, 691 patients, 6 full-article). The 30-day major bleeding pooled rate was 2.71% (95% CI: 1.51–4.83; I 2 =0%; 406 patients, 6 full-article), and the 30-day recurrent VTE pooled rate was 1.26% (95% CI: 0.53–3.00; I 2 =0%; 396 patients, 5 full-article). Conclusion Selected patients with cancer-associated PE managed as outpatients appear to have low short-term rates of mortality, major bleeding and recurrent VTE suggesting this may be a safe strategy. Further research with larger, prospective studies is needed to confirm these findings and refine risk stratification protocols.
Transcriptomics of interstitial lung disease: a systematic review and meta-analysis
Authors: Daniel He, Sabina A. Guler, Casey P. Shannon, Christopher J. Ryerson, Scott J. Tebbutt
Journal: European Respiratory Journal (2024)

Objective Gene expression (transcriptomics) studies have revealed potential mechanisms of interstitial lung disease (ILD), yet sample sizes of studies are often limited and between-subtype comparisons are scarce. The aim of this study was to identify and validate consensus transcriptomic signatures of ILD subtypes. Methods We performed a systematic review and meta-analysis of fibrotic ILD transcriptomics studies using an individual participant data approach, and included studies examining bulk transcriptomics of human adult ILD samples and excluding those focusing on individual cell populations. Patient-level data and expression matrices were extracted from 43 studies and integrated using a multivariable integrative algorithm to develop ILD classification models. Results Using 1459 samples from 24 studies, we identified transcriptomic signatures for idiopathic pulmonary fibrosis (IPF), hypersensitivity pneumonitis (HP), idiopathic nonspecific interstitial pneumonia (NSIP), and systemic sclerosis-associated ILD (SSc-ILD) against control samples, which were validated on 308 samples from 8 studies (area under receiver operating curve [AUC]=0.99 [95% CI: 0.99–1.00], HP AUC=0.91 [0.84–0.99], NSIP AUC=0.94 [0.88–0.99], SSc-ILD AUC=0.98 [0.93–1.00]). Significantly, meta-analysis allowed, for the first time, identification of robust lung transcriptomics signatures to discriminate IPF (AUC=0.71 [0.63–0.79]) and HP (AUC=0.76 [0.63–0.89]) from other fibrotic ILDs, and unsupervised learning algorithms identified putative molecular endotypes of ILD associated with decreased forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (D LCO ) % predicted. Transcriptomics signatures were reflective of both cell-specific and disease-specific changes in gene expression. Conclusion We present the first systematic review and largest meta-analysis of fibrotic ILD transcriptomics to date, identifying reproducible transcriptomic signatures with clinical relevance.
Hypoxia-inducible factor 2α promotes pathogenic polarization of stem-like Th2 cells via modulation of phospholipid metabolism
Authors: Xinkai Zou, Keyue Wang, Yujun Deng, Pengbo Guan, Qianlun Pu, Yuemeng Wang, Jun Mou, Yizhou Du, Xiaoxian Lou, Sijiao Wang, Na Jiang, Shengtao Zhou, Hui Wang, Dan Du, Xindong Liu, Hongbo Hu, Huiyuan Zhang
Journal: Immunity (2024)

T helper 2 (Th2) cells orchestrate immunity against parasite infection and promote tissue repair but promote pathology in asthma and tissue fibrosis. Here, we examined the mechanisms driving pathogenic differentiation of Th2 cells. Single-cell analyses of CD4+ T cells from asthma and chronic rhinosinusitis patients revealed high expression of the hypoxia-inducible factor (HIF)2α in Th2 cells. In mice, HIF2α deficiency impaired Th2 differentiation and alleviated asthmatic inflammation. Single-cell and lineage tracing approaches delineated a differentiation trajectory from TCF1+Ly108+ stem-like Th2 cells to the ST2+CD25+ pathogenic progeny, depending on a HIF2α-GATA3 circuit that modulated phospholipid metabolism and T cell receptor (TCR)-phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT) activation via transcriptional regulation of the inositol polyphosphate multikinase (IPMK). Overexpression of IPMK in HIF2α-deficient cells promoted Phosphatidylinositol (3,4,5)-trisphosphate (PIP3) synthesis and pathogenic Th2 cell differentiation, whereas pharmacological inhibition of HIF2α impaired pathogenic differentiation of Th2 cells and mitigated airway inflammation. Our findings provide insight into the contextual cues that promote Th2-mediated pathology and suggest HIF2α as a therapeutic target in asthma.
Integrative pathway analysis across humans and 3D cellular models identifies the p38 MAPK-MK2 axis as a therapeutic target for Alzheimer’s disease
Authors: Pourya Naderi Yeganeh, Sang Su Kwak, Mehdi Jorfi, Katjuša Koler, Thejesh Kalatturu, Djuna von Maydell, Zhiqing Liu, Kevin Guo, Younjung Choi, Joseph Park, Nelson Abarca, Grisilda Bakiasi, Murat Cetinbas, Ruslan Sadreyev, Ana Griciuc, Luisa Quinti, Se Hoon Choi, Weiming Xia, Rudolph E Tanzi, Winston Hide, Doo Yeon Kim
Journal: Neuron (2024)
Phase separation of chimeric antigen receptor promotes immunological synapse maturation and persistent cytotoxicity
Authors: Xinyi Xu, Haotian Chen, Zhengxu Ren, Xiaomin Xu, Wei Wu, Haochen Yang, JinJiao Wang, Yumeng Zhang, Qiuping Zhou, Hua Li, Shaoqing Zhang, Haopeng Wang, Chenqi Xu
Journal: Immunity (2024)
Zinc promotes microbial p-coumaric acid production that protects against cholestatic liver injury
Authors: Dongping Li, Meijuan Wan, Lanfeng Xue, Zhelin Zhang, Yifeng Qiu, Fengyi Mei, Niexing Tang, Chunxiao Yu, Yao Yu, Tianqi Chen, Xing Ding, Qin Yang, Qiuyan Liu, Peng Gu, Wei Jia, Yu Chen, Peng Chen
Journal: Cell Host & Microbe (2024)
Synovial tissue myeloid dendritic cell subsets exhibit distinct tissue-niche localization and function in health and rheumatoid arthritis
Authors: Lucy MacDonald, Aziza Elmesmari, Domenico Somma, Jack Frew, Clara Di Mario, Roopa Madhu, Audrey Paoletti, Theodoros Simakou, Olympia M Hardy, Barbara Tolusso, Denise Campobasso, Simone Perniola, Marco Gessi, Maria Rita Gigante, Luca Petricca, Dario Bruno, Lavinia Agra Coletto, Roberta Benvenuto, John D Isaacs, Andrew Filby, David McDonald, Jasmine P X Sim, Nigel Jamieson, Kevin Wei, Maria Antonietta D'Agostino, Neal L Millar, Simon Milling, Charles McSharry, Elisa Gremese, Karen Affleck, Kenneth F Baker, Iain B McInnes, Thomas D Otto, Ilya Korsunsky, Stefano Alivernini, Mariola Kurowska-Stolarska
Journal: Immunity (2024)

Current rheumatoid arthritis (RA) treatments do not restore immune tolerance. Investigating dendritic cell (DC) populations in human synovial tissue (ST) may reveal pathways to reinstate tolerance in RA. Using single-cell and spatial transcriptomics of ST biopsies, as well as co-culture systems, we identified condition- and niche-specific DC clusters with distinct functions. Healthy tissue contained tolerogenic AXL
Type 1 Immune Responses Related to Viral Infection Influence Corticosteroid Response in Asthma
Authors: John V Fahy, Nathan D. Jackson, Satria P. Sajuthi, Elmar Pruesse, Camille M. Moore, Jamie L. Everman, Cydney Rios, Monica Tang, Marc Gauthier, Sally E. Wenzel, Eugene R. Bleecker, Mario Castro, Suzy A Comhair, Serpil C Erzurum, Annette T. Hastie, Wendy Moore, Elliot Israel, Bruce D. Levy, Loren Denlinger, Nizar N Jarjour, Mats W. Johansson, David T Mauger, Brenda R. Phillips, Kaharu Sumino, Prescott G. Woodruff, Michael C. Peters, Max A Seibold
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

Rationale: Corticosteroid-responsive type 2 (T2) inflammation underlies the T2-high asthma endotype. However, we hypothesized that type 1 (T1) inflammation, possibly related to viral infection, may also influence corticosteroid response. Objectives: To determine the frequency and within-patient variability of T1-high, T2-high, and T1/T2-high asthma endotypes and whether virally influenced T1-high disease influences corticosteroid response in asthma. Methods: Patients in SARP-3 (Severe Asthma Research Program-3) had sputum collected at baseline, after intramuscular (triamcinolone acetonide) corticosteroid treatment, and at 1- and 3-year follow-ups. Sputum cell RNA was used for whole-transcriptome gene network and viral metagenomic analyses. We then profiled patients as highly expressing T1 and/or T2 gene networks and established the influence of these endotypes on corticosteroid responsiveness and the likelihood of viral transcript detection in the airways. Measurements and Main Results: We found that 22% and 35% of patients with asthma highly expressed T1 and T2 network genes, respectively, and that 8.5% highly expressed both networks. Asthma severity outcomes were worse in T2-high compared with T1-high asthma and most severe in the T1-high/T2-high subgroup. Corticosteroid treatment strongly suppressed T2 but poorly suppressed T1 gene expression, and corticosteroid-associated improvements in FEV1 occurred only in patients with T1-low/T2-high disease and not in patients with T1-high/T2-high disease. Viral metagenomic analyses uncovered that 24% of asthma sputum samples tested positive for a respiratory virus, and high viral carriage was associated with 14-fold increased risk of T1-high disease. Conclusions: Airway T1 immune responses are relatively common in asthma, are largely corticosteroid resistant, and are associated with subclinical viral infection.
Genome-wide investigation of VNTR motif polymorphisms in 8,222 genomes: Implications for biological regulation and human traits
Authors: Sijia Zhang, Qiao Song, Peng Zhang, Xiaona Wang, Rong Guo, Yanyan Li, Shuai Liu, Xiaoyu Yan, Jingjing Zhang, Yiwei Niu, Yirong Shi, Tingrui Song, Tao Xu, Shunmin He
Journal: Cell Genomics (2024)

Variable number tandem repeat (VNTR) is a pervasive and highly mutable genetic feature that varies in both length and repeat sequence. Despite the well-studied copy-number variants, the functional impacts of repeat motif polymorphisms remain unknown. Here, we present the largest genome-wide VNTR polymorphism map to date, with over 2.5 million VNTR length polymorphisms (VNTR-LPs) and over 11 million VNTR motif polymorphisms (VNTR-MPs) detected in 8,222 high-coverage genomes. Leveraging the large-scale NyuWa cohort, we identified 2,982,456 (31.8%) NyuWa-specific VNTR-MPs, of which 95.3% were rare. Moreover, we found 1,937 out of 38,685 VNTRs that were associated with gene expression through VNTR-MPs in lymphoblastoid cell lines. Specifically, we clarified that the expansion of a likely causal motif could upregulate gene expression by improving the binding concentration of PU.1. We also explored the potential impacts of VNTR polymorphisms on phenotypic differentiation and disease susceptibility. This study expands our knowledge of VNTR-MPs and their functional implications.
<i>Notes from the Field:</i> Increase in Diagnoses of Human Parvovirus B19–Associated Aplastic Crises in Children and Adolescents with Sickle Cell Disease — Atlanta, Georgia, December 14, 2023–September 30, 2024
Authors: Marianne E.M. Yee, Grace G. Kalmus, Ashwin P. Patel, Jason N. Payne, Amy Tang, Beatrice E. Gee
Journal: MMWR Morbidity and Mortality Weekly Report (2024)
Human Pulmonary Neuroendocrine Cells Respond to House Dust Mite Extract With <scp>PAR</scp>‐1 Dependent Release of <scp>CGRP</scp>
Authors: Ritu Mann‐Nüttel, Shivani Mandal, Marie Armbruster, Lakshmi Puttagunta, Paul Forsythe
Journal: Allergy (2024)

ABSTRACT Background Pulmonary neuroendocrine cells (PNEC) are rare airway epithelial cells that have recently gained attention as potential amplifiers of allergic asthma. However, studying PNEC function in humans has been challenging due to a lack of cell isolation methods, and little is known about human PNEC function in response to asthma‐relevant stimuli. Here we developed and characterized an in vitro human PNEC model and investigated the neuroendocrine response to extracts of the common aeroallergen house dust mite (HDM). Methods PNEC‐enriched cultures were generated from human induced pluripotent stem cells (iPNEC) and primary bronchial epithelial cells (ePNEC). Characterized PNEC cultures were exposed to HDM extract, a volatile chemical odorant (Bergamot oil), or the bacterial membrane component, lipopolysaccharide (LPS), and neuroendocrine gene expression and neuropeptide release determined. Results Both iPNEC and ePNEC models demonstrated similar baseline neuroendocrine characteristics and a stimuli‐specific modulation of gene expression. Most notably, exposure to HDM but not Bergamot oil or LPS, leads to dose‐dependent induction of the CGRP encoding gene, CALCB, and corresponding release of the neuropeptide. HDM‐induced CALCB expression and CGRP release could be inhibited by a protease‐activated receptor 1 (PAR1) antagonist or protease inhibitors and was mimicked by a PAR1 agonist. Conclusions We have characterized a novel model of PNEC‐enriched human airway epithelium and utilized this model to demonstrate a previously unrecognized role for human PNEC in mediating a direct neuroendocrine response to aeroallergen exposure.
Ancestral differences in anti-cancer treatment efficacy and their underlying genomic and molecular alterations
Authors: Mei Luo, Jingwen Yang, Alejandro A. Schaffer, Chengxuan Chen, Yuan Liu, Yamei Chen, Chunru Lin, Lixia Diao, Yong Zang, Yanyan Lou, Huda Salman, Gordon B. Mills, Eytan Ruppin, Leng Han
Journal: Cancer Discovery (2024)

Our study charts a global landscape of ancestry-associated differences in therapeutic efficacy, highlighting the importance of considering ancestry in anticancer therapies.