tbuckley/cabot-search huggingface dataset:
Peptide-based urinary monitoring of fibrotic nonalcoholic steatohepatitis by mass-barcoded activity-based sensors
Authors: Sophie C. Cazanave, Andrew D. Warren, Maciej Pacula, Fayçal Touti, Anna Zagorska, Nil Gural, Eric K. Huang, Sarah Sherman, Mehar Cheema, Sabrina Ibarra, Jamie Bates, Andrew N. Billin, John T. Liles, Grant R. Budas, David G. Breckenridge, Dina Tiniakos, Vlad Ratziu, Ann K. Daly, Olivier Govaere, Quentin M. Anstee, Louis Gelrud, Jay Luther, Raymond T. Chung, Kathleen E. Corey, Wendy Winckler, Sangeeta Bhatia, Gabriel A. Kwong
Journal: Science Translational Medicine (2021)

Noninvasive detection of nonalcoholic steatohepatitis (NASH), the progressive form of nonalcoholic fatty liver disease, promises to improve patient screening, accelerate drug trials, and reduce health care costs. On the basis of protease dysregulation of the biological pathways of fibrotic NASH, we developed the Glympse Bio Test System (GBTS) for multiplexed quantification of liver protease activity. GBTS-NASH comprises a mixture of 19 mass-barcoded PEGylated peptides that is administered intravenously and senses liver protease activity by releasing mass-barcoded reporters into urine for analysis by mass spectrometry. To identify a protease signature of NASH, transcriptomic analysis of 355 human liver biopsies identified a 13-protease panel that discriminated clinically relevant NASH ≥F2 fibrosis from F0-F1 with high classification accuracy across two independent patient datasets. We screened 159 candidate substrates to identify a panel of 19 peptides that exhibited high activity for our 13-protease panel. In the choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) mouse model, binary classifiers trained on urine samples discriminated fibrotic NASH from simple steatosis and healthy controls across a range of nondisease conditions and indicated disease regression upon diet change [area under receiver operating characteristics (AUROCs) > 0.97]. Using a hepatoprotective triple combination treatment (FXR agonist, ACC and ASK1 inhibitors) in a rat model of NASH, urinary classification distinguished F0-F1 from ≥F2 animals and indicated therapeutic response as early as 1 week on treatment (AUROCs >0.91). Our results support GBTS-NASH to diagnose fibrotic NASH via an infusion of peptides, monitor changes in disease severity, and indicate early treatment response.
IL-33-induced metabolic reprogramming controls the differentiation of alternatively activated macrophages and the resolution of inflammation
Authors: Maria Faas, Natacha Ipseiz, Jochen Ackermann, Stephan Culemann, Anika Grüneboom, Fenja Schröder, Tobias Rothe, Carina Scholtysek, Martin Eberhardt, Martin Böttcher, Philipp Kirchner, Cornelia Stoll, Arif Ekici, Maximilian Fuchs, Meik Kunz, Benno Weigmann, Stefan Wirtz, Roland Lang, Joerg Hofmann, Julio Vera, David Voehringer, Alessandro Michelucci, Dimitrios Mougiakakos, Stefan Uderhardt, Georg Schett, Gerhard Krönke
Journal: Immunity (2021)
Response to Comment on Choi et al. Alcohol Abstinence and the Risk of Atrial Fibrillation in Patients With Newly Diagnosed Type 2 Diabetes Mellitus: a Nationwide Population-Based Study. Diabetes Care 2021;44:1393–1401
Authors: You-jung Choi, Kyung-Do Han, So-Ryoung Lee, Eue-Keun Choi, Seil Oh, Gregory Y.H. Lip
Journal: Diabetes Care (2021)

We thank Lin et al. (1) for their interest in our article, which showed that abstainers from alcohol after diagnosis of type 2 diabetes had a lower risk of atrial fibrillation (AF) than the constant drinkers (2). Lin et al. suggested two issues with our article, namely, immortal time bias and drug-related confounding factors.

Immortal time bias is an issue in some observational studies when the treatment exposure occurred after the initiation of the study (3). Study subjects should survive long enough to receive treatment, so time-dependent events should be analyzed …
Abstract 14106: Association of Mildly Reduced Estimated Glomerular Filtration Rate With Clinical and Subclinical Cardiovascular Disease and Chronic Kidney Disease: The Framingham Heart Study
Authors: Feven Ataklte, Rebecca Song, Ashish Upadhyay, Vasan S Ramachandran, Vanessa Xanthakis
Journal: Circulation (2019)

Introduction: Chronic kidney disease (CKD) has a well-known association with excess cardiovascular disease (CVD) risk. However, data are limited on the association of mildly reduced estimated glome...
FP04.01 Nivolumab 480 mg Every 4 Weeks as De Novo Second-line Treatment for Advanced Non-Small Cell Lung Cancer: CheckMate 907
Authors: N. Leighl, A. Alexandru, Y. Ohe, P. Ruff, T. Hida, M. Nishio, J. Rothenstein, A. Tomiak, P. Lowry, T. Kumagai, I. Gore, I. Ntambwe, S. Marimuthu, M. Schenker
Journal: Journal of Thoracic Oncology (2021)
Acceptability of hygiene, face covering and social distancing interventions to prevent exacerbations in people living with airways diseases
Authors: John R Hurst, Andrew Cumella, Camila Nagoda Niklewicz, Keir E J Philip, Victoria Singh, Nicholas S Hopkinson
Journal: Thorax (2021)

Interventions to prevent the spread of SARS-CoV-2 have been associated with substantial reductions in exacerbations of airways diseases, likely through reduced transmission of other respiratory viruses. We surveyed 4442 people with airways disease (asthma=3627, bronchiectasis=258, chronic obstructive pulmonary disease=557) to gauge attitudes and intentions towards continuing such measures after the COVID-19 pandemic. 47% intended to continue wearing a face mask in indoor public spaces, and 61% thought everyone should be required to do so during the 'influenza season. Women, those with bronchiectasis, and older people were generally more cautious. Respiratory virus infection control measures should be considered in clinical guidelines and public health recommendations.
Transmission of trained immunity and heterologous resistance to infections across generations
Authors: Natalie Katzmarski, Jorge Domínguez-Andrés, Branko Cirovic, Georgios Renieris, Eleonora Ciarlo, Didier Le Roy, Konstantin Lepikhov, Kathrin Kattler, Gilles Gasparoni, Kristian Händler, Heidi Theis, Marc Beyer, Jos W. M. van der Meer, Leo A. B. Joosten, Jörn Walter, Joachim L. Schultze, Thierry Roger, Evangelos J. Giamarellos-Bourboulis, Andreas Schlitzer, Mihai G. Netea
Journal: Nature Immunology (2021)
P12.02 Systemic Anticancer Therapy Upregulate Plasma Levels of Damage-Associated Molecular Patterns in Patients With Advanced Lung Cancer
Authors: H. Inoue, H. Tsutsumi, K. Tanaka, E. Iwama, Y. Yoneshima, Y. Shiraishi, K. Ota, Y. Nakanishi, I. Okamoto
Journal: Journal of Thoracic Oncology (2021)
Lay people’s beliefs about creativity: evidence for an insight bias
Authors: Brian J. Lucas, Loran F. Nordgren
Journal: Trends in Cognitive Sciences (2021)

Research finds that creative ideas are generated by two cognitive pathways: insight and persistence. However, emerging research suggests people's lay beliefs may not adequately reflect both routes. We propose that people exhibit an insight bias, such that they undervalue persistence and overvalue insight in the creative process.
Days at Home After Transcatheter vs Surgical Aortic Valve Replacement in Intermediate-Risk Patients
Authors: Mabel Chung, Kamil F. Faridi, Dhruv S. Kazi, Zaid I. Almarzooq, Yang Song, Suzanne J. Baron, Robert W. Yeh
Journal: JAMA Cardiology (2021)

This comparative effectiveness research study uses Medicare claims data to examine the total number of days at home among intermediate-risk patients recovering from transcatheter aortic valve replacement (TAVR) vs patients recovering from surgical aortic valve replacement (SAVR).
Developing a mechanically matched decellularized spinal cord scaffold for the in situ matrix-based neural repair of spinal cord injury
Authors: Yuan-huan Ma, Hui-juan Shi, Qing-shuai Wei, Qing-wen Deng, Jia-hui Sun, Zhou Liu, Bi-qin Lai, Ge Li, Ying Ding, Wan-ting Niu, Yuan-shan Zeng, Xiang Zeng
Journal: Biomaterials (2021)
P16.05 Real World Data of First-Line Treatment With Pembrolizumab for Highly PD-L1-Expressing NSCLC
Authors: M. Kobayashi, H. Mizugaki, Y. Ikezawa, R. Morita, K. Tateishi, K. Yokoo, T. Sumi, H. Kikuchi, Y. Nagano, A. Nakamura, M. Aso, N. Kimura, F. Yoshiike, M. Furuta, H. Tanaka, M. Sekikawa, T. Hachiya, Y. Fujita, S. Oizumi
Journal: Journal of Thoracic Oncology (2021)
Pustular psoriasis: Molecular pathways and effects of spesolimab in generalized pustular psoriasis
Authors: Patrick Baum, Sudha Visvanathan, Sandra Garcet, Janine Roy, Ramona Schmid, Sebastian Bossert, Benjamin Lang, Hervé Bachelez, Robert Bissonnette, Christian Thoma, James G. Krueger
Journal: Journal of Allergy and Clinical Immunology (2021)

The IL-36 pathway plays a key role in the pathogenesis of generalized pustular psoriasis (GPP). In a proof-of-concept clinical trial, treatment with spesolimab, an anti-IL-36 receptor antibody, resulted in rapid skin and pustular clearance in patients presenting with GPP flares.We sought to compare the molecular profiles of lesional and nonlesional skin from patients with GPP or palmoplantar pustulosis (PPP) with skin from healthy volunteers, and to investigate the molecular changes after spesolimab treatment in the skin and blood of patients with GPP flares.Pre- and post-treatment skin and blood samples were collected from patients with GPP who participated in a single-arm, phase I study (n = 7). Skin biopsies from patients with PPP (n = 8) and healthy volunteers (n = 16) were obtained for comparison at baseline. Biomarkers were assessed by RNA-sequencing, histopathology, and immunohistochemistry.In GPP and PPP lesions, 1287 transcripts were commonly upregulated or downregulated. Selected transcripts from the IL-36 signaling pathway were upregulated in untreated GPP and PPP lesions. In patients with GPP, IL-36 pathway-related signatures, TH1/TH17 and innate inflammation signaling, neutrophilic mediators, and keratinocyte-driven inflammation pathways were downregulated by spesolimab as early as week 1. Spesolimab also decreased related serum biomarkers and cell populations in the skin lesions from patients with GPP, including CD3+ T, CD11c+, and IL-36γ+ cells and lipocalin-2-expressing cells.In patients with GPP, spesolimab showed rapid modulation of commonly dysregulated molecular pathways in GPP and PPP, which may be associated with improved clinical outcomes.
Cardiovascular Effects of Particulate Air Pollution
Authors: Aruni Bhatnagar
Journal: Annual Review of Medicine (2021)

Inhalation of fine particulate matter (PM 2.5 ), produced by the combustion of fossil fuels, is an important risk factor for cardiovascular disease. Exposure to PM 2.5 has been linked to increases in blood pressure, thrombosis, and insulin resistance. It also induces vascular injury and accelerates atherogenesis. Results from animal models corroborate epidemiological evidence and suggest that the cardiovascular effects of PM 2.5 may be attributable, in part, to oxidative stress, inflammation, and the activation of the autonomic nervous system. Although the underlying mechanisms remain unclear, there is robust evidence that long-term exposure to PM 2.5 is associated with premature mortality due to heart failure, stoke, and ischemic heart disease.
P68.05 Human Lung Carcinoma Primary Cultures From Malignant Pleural Effusions as a Tool for Drug Screening and Personalized Therapy
Authors: C. Aguado Esteban, B. García Peláez, C. Cabrera, S. Viteri, A. Aguilar-Hernández, S. Rodríguez, E. Aldeguer, L. Berrocal, R. Roman, P. Rubenstein, F. Garcia-Casabal, C. Mayo-De-Las-Casas, R. Rosell, M.A. Molina-Vila
Journal: Journal of Thoracic Oncology (2021)
Neuroprotective effects of minocycline and KML29, a potent inhibitor of monoacylglycerol lipase, in an experimental stroke model: a small-animal positron emission tomography study
Authors: Tomoteru Yamasaki, Akiko Hatori, Yiding Zhang, Wakana Mori, Yusuke Kurihara, Masanao Ogawa, Hidekatsu Wakizaka, Jian Rong, Lu Wang, Steven Liang, Ming-Rong Zhang
Journal: Theranostics (2021)

Hypoxia caused by ischemia induces acidosis and neuroexcitotoxicity, resulting in neuronal death in the central nervous system (CNS). Monoacylglycerol lipase (MAGL) is a modulator of 2-arachidonoylglycerol (2-AG), which is involved in retrograde inhibition of glutamate release in the endocannabinoid system. In the present study, we used positron emission tomography (PET) to monitor MAGL-positive neurons and neuroinflammation in the brains of ischemic rats. Additionally, we performed PET imaging to evaluate the neuroprotective effects of an MAGL inhibitor in an ischemic injury model. Methods: Ischemic-injury rat models were induced by intraluminal right middle cerebral artery occlusion (MCAO). PET studies of the brains of the ischemic rats were performed at several experimental time points (pre-occlusion, days 2, 4, and 7 after the MCAO surgery) using [11C]SAR127303 for MAGL and [18F]FEBMP for 18 kDa translocator protein (TSPO, a hall-mark of neuroinflammation). Medication using minocycline (a well-known neuroprotective agent) or KML29 (a potent MAGL inhibitor) was given immediately after the MCAO surgery and then daily over the subsequent three days. Results: PET imaging of the ischemic rats using [11C]SAR127303 showed an acute decline of radioactive accumulation in the ipsilateral side at two days after MCAO surgery (ratio of the area under the curve between the ipsilateral and contralateral sides: 0.49 ± 0.04 in the cortex and 0.73 ± 0.02 in the striatum). PET imaging with [18F]FEBMP, however, showed a moderate increase in accumulation of radioactivity in the ipsilateral hemisphere on day 2 (1.36 ± 0.11), and further increases on day 4 (1.72 ± 0.15) and day 7 (1.99 ± 0.06). Treatment with minocycline or KML29 eased the decline in radioactive accumulation of [11C]SAR127303 for MAGL (minocycline-treated group: 0.82 ± 0.06 in the cortex and 0.81 ± 0.05 in the striatum; KML29-treated group: 0.72 ± 0.07 in the cortex and 0.88 ± 0.04 in the striatum) and increased uptake of [18F]FEBMP for TSPO (minocycline-treated group: 1.52 ± 0.21 in the cortex and 1.56 ± 0.11 in the striatum; KML29-treated group: 1.63 ± 0.09 in the cortex and 1.50 ± 0.17 in the striatum). In MCAO rats, minocycline treatment showed a neuroprotective effect in the sensorimotor cortex suffering from severe hypoxic injury, whereas KML29 treatment saved neurons in the striatum, including bundles of myelinated axons. Conclusions: PET imaging allowed visualization of the different neuroprotective effects of minocycline and KML29, and indicated that combination pharmacotherapy using these drugs may be an effective therapy in acute ischemia.
Estrogen-induced transformation of human breast epithelial cells involves mutations in mismatch repair genes
Authors: Patricia A. Russo, Gabriela A. Balogh, Irma H. Russo, Jose Russo
Journal: Cancer Research (2004)

2629  The association found between breast cancer development and prolonged exposure to estrogens suggests that this hormone is of etiologic importance in the causation of this disease. We have previously demonstrated that 17β-estradiol (E2), like the carcinogen benz(a)pyrene (BP), induces in human breast epithelial cells (HBEC) phenotypes indicative of neoplastic transformation, such colony formation in agar methocel, or colony efficiency and loss of ductulogenesis in collagen matrix. We postulate that a possible mechanism through which estrogens induce cell transformation involves the DNA repair system. For testing this hypothesis, in the present study we investigated whether E2 induces defects or mutagenesis in the mismatch repair (MMR) genes MLH1, MSH2, PMS1, PMS2 and MSH6. For this purpose, the immortal human breast epithelial cells MCF-10F cells grown in DMEM medium in the presence of high calcium concentration were treated with 70 nM E2 for two weeks. When the flasks were 85% confluent RNA was extracted. RT-PCR assays were performed using specific primers for the MMR genes described, and the products were analyzed for mutations by cDNA sequencing using the CEQ 8000 (Beckman Coulter) employing both sense and antisense sequence primers for each gene. We found that E2 induced the following mutations in MMR genes: in MSH2, 3 missense mutations located in nucleotides 1960 and 1963, one insertion of thymine in nucleotide 1988, and one non-sense mutation in nucleotide 1996, which are responsible for the stop codon in the protein sequence by change Glu (GAA) by stop codon (TGA); in PMS1, 7 mutations located between nucleotides 2314 and 2331; in PMS2, 4 missense mutations located in nucleotides 1407, 1408, 1409 and 1454, 3 thymine insertions in nucleotides 1390, 1406 and 1432 and one non-sense mutation located in codon 464 by change Asp (GAC) by stop codon (TGA), and in MSH6, 5 mutations located from nucleotides 27491 to 3021. No mutations were found in MLH1 gene. Our results indicated that effectively, E2 at a dose of 70nM exerts a mutagenic effect on the MMR repair genes and that this mechanism might be responsible of the induction of HBEC transformation. (This work was supported by grants DMAD17-00-1-0247, DMAD17-03-1-0229).
G<i>α</i>s–Protein Kinase A (PKA) Pathway Signalopathies: The Emerging Genetic Landscape and Therapeutic Potential of Human Diseases Driven by Aberrant G<i>α</i>s-PKA Signaling
Authors: Dana J. Ramms, Francesco Raimondi, Nadia Arang, Friedrich W. Herberg, Susan S. Taylor, J. Silvio Gutkind
Journal: Pharmacological Reviews (2021)

Many of the fundamental concepts of signal transduction and kinase activity are attributed to the discovery and crystallization of cAMP-dependent protein kinase, or protein kinase A. PKA is one of the best-studied kinases in human biology, with emphasis in biochemistry and biophysics, all the way to metabolism, hormone action, and gene expression regulation. It is surprising, however, that our understanding of PKA's role in disease is largely underappreciated. Although genetic mutations in the PKA holoenzyme are known to cause diseases such as Carney complex, Cushing syndrome, and acrodysostosis, the story largely stops there. With the recent explosion of genomic medicine, we can finally appreciate the broader role of the G<i>α</i>s-PKA pathway in disease, with contributions from aberrant functioning G proteins and G protein–coupled receptors, as well as multiple alterations in other pathway components and negative regulators. Together, these represent a broad family of diseases we term the G<i>α</i>s-PKA pathway signalopathies. The G<i>α</i>s-PKA pathway signalopathies encompass diseases caused by germline, postzygotic, and somatic mutations in the G<i>α</i>s-PKA pathway, with largely endocrine and neoplastic phenotypes. Here, we present a signaling-centric review of G<i>α</i>s-PKA–driven pathophysiology and integrate computational and structural analysis to identify mutational themes commonly exploited by the G<i>α</i>s-PKA pathway signalopathies. Major mutational themes include hotspot activating mutations in Gαs, encoded by <i>GNAS,</i> and mutations that destabilize the PKA holoenzyme. With this review, we hope to incite further study and ultimately the development of new therapeutic strategies in the treatment of a wide range of human diseases. <h3>Significance Statement</h3> Little recognition is given to the causative role of G<i>α</i>s-PKA pathway dysregulation in disease, with effects ranging from infectious disease, endocrine syndromes, and many cancers, yet these disparate diseases can all be understood by common genetic themes and biochemical signaling connections. By highlighting these common pathogenic mechanisms and bridging multiple disciplines, important progress can be made toward therapeutic advances in treating G<i>α</i>s-PKA pathway–driven disease.
ORTHOSCOPE*: A Phylogenetic Pipeline to Infer Gene Histories from Genome-Wide Data
Authors: Jun Inoue
Journal: Molecular Biology and Evolution (2021)

Abstract Comparative genome-scale analyses of protein-coding gene sequences are employed to examine evidence for whole-genome duplication and horizontal gene transfer. For this purpose, an orthogroup should be delineated to infer evolutionary history regarding each gene, and results of all orthogroup analyses need to be integrated to infer a genome-scale history. An orthogroup is a set of genes descended from a single gene in the last common ancestor of all species under consideration. However, such analyses confront several problems: 1) Analytical pipelines to infer all gene histories with methods comparing species and gene trees are not fully developed, and 2) without detailed analyses within orthogroups, evolutionary events of paralogous genes in the same orthogroup cannot be distinguished for genome-wide integration of results derived from multiple orthogroup analyses. Here I present an analytical pipeline, ORTHOSCOPE* (star), to infer evolutionary histories of animal/plant genes from genome-scale data. ORTHOSCOPE* estimates a tree for a specified gene, detects speciation/gene duplication events that occurred at nodes belonging to only one lineage leading to a species of interest, and then integrates results derived from gene trees estimated for all query genes in genome-wide data. Thus, ORTHOSCOPE* can be used to detect species nodes just after whole-genome duplications as a first step of comparative genomic analyses. Moreover, by examining the presence or absence of genes belonging to species lineages with dense taxon sampling available from the ORTHOSCOPE web version, ORTHOSCOPE* can detect genes lost in specific lineages and horizontal gene transfers. This pipeline is available at https://github.com/jun-inoue/ORTHOSCOPE_STAR.
Long‐term safety of risankizumab from 17 clinical trials in patients with moderate‐to‐severe plaque psoriasis*
Authors: K.B. Gordon, M. Lebwohl, K.A. Papp, H. Bachelez, J.J. Wu, R.G. Langley, A. Blauvelt, B. Kaplan, M. Shah, Y. Zhao, R. Sinvhal, K. Reich
Journal: British Journal of Dermatology (2021)

Risankizumab has demonstrated efficacy and safety in patients with moderate-to-severe plaque psoriasis in randomized clinical trials.To evaluate safety data from risankizumab psoriasis phase I-III clinical trials.Short-term safety (through week 16) was analysed using integrated data from five phase II and III clinical trials. Long-term safety was evaluated using integrated data from 17 phase I-III completed and ongoing trials.Short-term safety analyses included 1306 patients receiving risankizumab 150 mg and 300 patients receiving placebo [402·2 and 92·0 patient-years (PY) of exposure, respectively]. Long-term analyses included 3072 risankizumab-treated patients (exposure: 7927 PY). The median (excluding four outliers) treatment duration was 2·9 years (range 2 days to 5·9 years). Exposure-adjusted adverse event rates did not increase with long-term treatment (318 vs. 171 events per 100 PY for short- and long-term analyses). With long-term risankizumab treatment, rates of serious adverse events were 7·8 per 100 PY, serious infections 1·2 per 100 PY, nonmelanoma skin cancer (NMSC) 0·7 per 100 PY, malignant tumours excluding NMSC 0·5 per 100 PY, and adjudicated major adverse cardiovascular events 0·3 per 100 PY, with no important identified risks. Limitations include that the study inclusion and exclusion criteria varied and that three studies enrolled ≤ 50 patients.Risankizumab demonstrated a favourable safety profile over short- and long-term treatment in patients with moderate-to-severe psoriasis.
MA06.05 Patterns of Care in Maintenance Therapy in U.S. Patients Undergoing Definitive Chemoradiation for Stage 3 Non-Small Cell Lung Cancer (NCSLC)
Authors: J. Liu, E. Bratton, X. Yu, C. Ladbury, J. Wagner, M. Small, A. Amini
Journal: Journal of Thoracic Oncology (2021)
P40.09 Using Real World Data to Identify a Patient Cohort Who Require Prehabilitation to Improve Treatment Rates for Stage 3 NSCLC
Authors: B.W.A. Langley, A. Horne, G. Tramonti, A. Patrizio, P. Hall, C. Lilley, M. Mackean, S. Campbell, T. Evans, A. Tufail, K. Maclennan, C. Barrie, I. Phillips
Journal: Journal of Thoracic Oncology (2021)