tbuckley/cabot-search huggingface dataset:
Deep Learning Radiomics Based on Contrast-Enhanced Ultrasound Might Optimize Curative Treatments for Very-Early or Early-Stage Hepatocellular Carcinoma Patients
Authors: Fei Liu, Dan Liu, Kun Wang, Xiaohua Xie, Liya Su, Ming Kuang, Guangliang Huang, Baogang Peng, Yuqi Wang, Manxia Lin, Jie Tian, Xiaoyan Xie
Journal: Liver Cancer (2020)

We aimed to evaluate the performance of a deep learning (DL)-based Radiomics strategy designed for analyzing contrast-enhanced ultrasound (CEUS) to not only predict the progression-free survival (PFS) of radiofrequency ablation (RFA) and surgical resection (SR) but also optimize the treatment selection between them for patients with very-early or early-stage hepatocellular carcinoma (HCC).We retrospectively enrolled 419 patients examined by CEUS within 1 week before receiving RFA or SR (RFA: 214, SR: 205) from January 2008 to 2016. Two Radiomics signatures were constructed by the Radiomics model R-RFA and R-SR to stratify PFS of different treatment groups. Then, RFA and SR nomograms were built by incorporating Radiomics signatures and significant clinical variables to achieve individualized 2-year PFS prediction. Finally, we applied both Radiomics models and both nomograms to each enrolled patient to investigate whether there were space for treatment optimization and how much prognostic improvement could be expected.R-RFA and R-SR showed remarkable discrimination (C-index: 0.726 for RFA, 0.741 for SR). RFA and SR nomograms provided good 2-year PFS prediction accuracy and good calibrations. We identified 17.3% RFA patients and 27.3% SR patients should swap their treatment, so their average probability of 2-year PFS would increase 12 and 15%, respectively.The proposed Radiomics models and nomograms achieved accurate preoperative prediction of PFS for RFA and SR, and they could facilitate the optimized treatment selection between them for patients with very-early or early-stage HCC.
Transcriptional and cytopathological hallmarks of FSHD in chronic DUX4-expressing mice
Authors: Darko Bosnakovski, Ahmed S. Shams, Ce Yuan, Meiricris T. da Silva, Elizabeth T. Ener, Cory W. Baumann, Angus J. Lindsay, Mayank Verma, Atsushi Asakura, Dawn A. Lowe, Michael Kyba
Journal: Journal of Clinical Investigation (2020)

Facioscapulohumeral muscular dystrophy (FSHD) is caused by loss of repression of the DUX4 gene; however, the DUX4 protein is rare and difficult to detect in human muscle biopsies, and pathological mechanisms are obscure. FSHD is also a chronic disease that progresses slowly over decades. We used the sporadic, low-level, muscle-specific expression of DUX4 enabled by the iDUX4pA-HSA mouse to develop a chronic long-term muscle disease model. After 6 months of extremely low sporadic DUX4 expression, dystrophic muscle presented hallmarks of FSHD histopathology, including muscle degeneration, capillary loss, fibrosis, and atrophy. We investigated the transcriptional profile of whole muscle as well as endothelial cells and fibroadiopogenic progenitors (FAPs). Strikingly, differential gene expression profiles of both whole muscle and, to a lesser extent, FAPs, showed significant overlap with transcriptional profiles of MRI-guided human FSHD muscle biopsies. These results demonstrate a pathophysiological similarity between disease in muscles of iDUX4pA-HSA mice and humans with FSHD, solidifying the value of chronic rare DUX4 expression in mice for modeling pathological mechanisms in FSHD and highlighting the importance FAPs in this disease.
T cell receptor repertoire characteristics both before and following immunotherapy correlate with clinical response in mesothelioma
Authors: Heleen Vroman, Giulia Balzaretti, Robert A Belderbos, Paul L Klarenbeek, Menno van Nimwegen, Koen Bezemer, Robin Cornelissen, Ilse T G Niewold, Barbera D van Schaik, Antione H van Kampen, Joachim G J V Aerts, Niek de Vries, Rudi W Hendriks
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Malignant pleural mesothelioma (MPM) is a highly lethal malignancy in need for new treatment options. Although immunotherapies have been shown to boost a tumor-specific immune response, not all patients respond and prognostic biomarkers are scarce. In this study, we determined the peripheral blood T cell receptor β (TCRβ) chain repertoire of nine MPM patients before and 5 weeks after the start of dendritic cell (DC)-based immunotherapy. Materials and methods We separately profiled PD1 + and PD1 − CD4 + and CD8 + T cells, as well as Tregs and analyzed 70 000 TCRβ sequences per patient. Results Strikingly, limited TCRβ repertoire diversity and high average clone sizes in total CD3 + T cells before the start of immunotherapy were associated with a better clinical response. To explore the differences in TCRβ repertoire prior-DC-therapy and post-DC-therapy, for each patient the TCRβ clones present in the total CD3 + T cell fractions were classified into five categories, based on therapy-associated frequency changes: expanding, decreasing, stable, newly appearing and disappearing clones. Subsequently, the presence of these five groups of clones was analyzed in the individual sorted T cell fractions. DC-therapy primarily induced TCRβ repertoire changes in the PD1 + CD4 + and PD1 + CD8 + T cell fractions. In particular, in the PD1 + CD8 + T cell subpopulation we found high frequencies of expanding, decreasing and newly appearing clones. Conversion from a PD1 − to a PD1 + phenotype was significantly more frequent in CD8 + T cells than in CD4 + T cells. Hereby, the number of expanding PD1 + CD8 + T cell clones—and not expanding PD1 + CD4 + T cell clones following immunotherapy positively correlated with overall survival, progression-free survival and reduction of tumor volume. Conclusion We conclude that the clinical response to DC-mediated immunotherapy is dependent on both the pre-existing TCRβ repertoire of total CD3 + T cells and on therapy-induced changes, in particular expanding PD1 + CD8 + T cell clones. Therefore, TCRβ repertoire profiling in sorted T cell subsets could serve as predictive biomarker for the selection of MPM patients that benefit from immunotherapy. Trial registration number NCT02395679 .
Pathogenic Activation of Mesenchymal Stem Cells Is Induced by the Disease Microenvironment in Systemic Sclerosis
Authors: Zeinab Taki, Elena Gostjeva, William Thilly, Bodoor Yaseen, Henry Lopez, Maria Mirza, Zainab Hassuji, Shivanee Vigneswaran, Bahja Ahmed Abdi, Amy Hart, Nikita Arumalla, Gemma Thomas, Christopher P. Denton, Yasir Suleman, Huan Liu, Cristina Venturini, Steven O'Reilly, Shiwen Xu, Richard Stratton
Journal: Arthritis & Rheumatology (2020)

In systemic sclerosis (SSc), a persistent tissue repair process leads to progressive fibrosis of the skin and internal organs. The role of mesenchymal stem cells (MSCs), which characteristically initiate and regulate tissue repair, has not been fully evaluated. We undertook this study to investigate whether dividing metakaryotic MSCs are present in SSc skin and to examine whether exposure to the disease microenvironment activates MSCs and leads to transdifferentiation.Skin biopsy material from patients with recent-onset diffuse SSc was examined by collagenase spread of 1-mm-thick surface-parallel sections, in order to identify dividing metakaryotic stem cells in each tissue plane. Adipose-derived MSCs from healthy controls were treated with dermal blister fluid (BF) from patients with diffuse SSc and profiled by next-generation sequencing, or they were evaluated for phenotypic changes relevant to SSc. Differential responses of dermal fibroblasts were studied in parallel.MSC-like cells undergoing active metakaryotic division were identified in SSc sections (but not control sections) most prominently in the deep dermis and adjacent to damaged microvessels, in both clinically involved and uninvolved skin. Furthermore, exposure to SSc BF caused selective MSC activation, inducing a myofibroblast signature, while reducing signatures of vascular repair and adipogenesis and enhancing migration and contractility. Microenvironmental factors implicated in inducing transdifferentiation included the profibrotic transforming growth factor β, the presence of lactate, and mechanosensing, while the microenvironment Th2 cytokine, interleukin-31, enhanced osteogenic commitment (calcinosis).Dividing MSC-like cells are present in the SSc disease microenvironment where multiple factors, likely acting in concert, promote transdifferentiation and lead to a complex and resistant disease state.
Timing of Endoscopy for Acute Upper Gastrointestinal Bleeding
Authors: James Y.W. Lau, Yuanyuan Yu, Raymond S.Y. Tang, Heyson C.H. Chan, Hon-Chi Yip, Shannon M. Chan, Sally W.Y. Luk, Sunny H. Wong, Louis H.S. Lau, Rashid N. Lui, Ting T. Chan, Joyce W.Y. Mak, Francis K.L. Chan, Joseph J.Y. Sung
Journal: New England Journal of Medicine (2020)

It is recommended that patients with acute upper gastrointestinal bleeding undergo endoscopy within 24 hours after gastroenterologic consultation. The role of endoscopy performed within time frames shorter than 24 hours has not been adequately defined.To evaluate whether urgent endoscopy improves outcomes in patients predicted to be at high risk for further bleeding or death, we randomly assigned patients with overt signs of acute upper gastrointestinal bleeding and a Glasgow-Blatchford score of 12 or higher (scores range from 0 to 23, with higher scores indicating a higher risk of further bleeding or death) to undergo endoscopy within 6 hours (urgent-endoscopy group) or between 6 and 24 hours (early-endoscopy group) after gastroenterologic consultation. The primary end point was death from any cause within 30 days after randomization.A total of 516 patients were enrolled. The 30-day mortality was 8.9% (23 of 258 patients) in the urgent-endoscopy group and 6.6% (17 of 258) in the early-endoscopy group (difference, 2.3 percentage points; 95% confidence interval [CI], -2.3 to 6.9). Further bleeding within 30 days occurred in 28 patients (10.9%) in the urgent-endoscopy group and in 20 (7.8%) in the early-endoscopy group (difference, 3.1 percentage points; 95% CI, -1.9 to 8.1). Ulcers with active bleeding or visible vessels were found on initial endoscopy in 105 of the 158 patients (66.4%) with peptic ulcers in the urgent-endoscopy group and in 76 of 159 (47.8%) in the early-endoscopy group. Endoscopic hemostatic treatment was administered at initial endoscopy for 155 patients (60.1%) in the urgent-endoscopy group and for 125 (48.4%) in the early-endoscopy group.In patients with acute upper gastrointestinal bleeding who were at high risk for further bleeding or death, endoscopy performed within 6 hours after gastroenterologic consultation was not associated with lower 30-day mortality than endoscopy performed between 6 and 24 hours after consultation. (Funded by the Health and Medical Fund of the Food and Health Bureau, Government of Hong Kong Special Administrative Region; ClinicalTrials.gov number, NCT01675856.).
The role of macrophage reprogramming induced by GRA15II, a polypeptide effector molecule of Toxoplasma gondii, in liver diseases in model mice
Authors: Yihong Cai, Yanxia Yu, Yanling Wang, Yuan Zhang, Qingli Luo, Li Yu, Jian Du, Deyong Chu, Jilong Shen
Journal: Cellular and Molecular Immunology (2020)
Preterm Birth among Infants Exposed to<i>in Utero</i>Ultrafine Particles from Aircraft Emissions
Authors: Sam E. Wing, Timothy V. Larson, Neelakshi Hudda, Sarunporn Boonyarattaphan, Scott Fruin, Beate Ritz
Journal: Environmental Health Perspectives (2020)

Introduction: Ambient air pollution is a known risk factor for adverse birth outcomes, but the role of ultrafine particles (UFPs) is not well understood. Aircraft-origin UFPs adversely affect air quality over large residential areas downwind of airports, but their reproductive health burden remains uninvestigated. Objectives: This analysis evaluated whether UFPs from jet aircraft emissions are associated with increased rates of preterm birth (PTB) among pregnant mothers living downwind of Los Angeles International Airport (LAX). Methods: This population-based study used birth records, provided by the California Department of Public Health, to ascertain birth outcomes and a novel, validated geospatial UFP dispersion model approach to estimate in utero exposures. All mothers who gave birth from 2008 to 2016 while living within 15km of LAX were included in this analysis (N=174,186; including 15,134 PTBs). Results: In utero exposure to aircraft-origin UFPs was positively associated with PTB. The odds ratio (OR) per interquartile range (IQR) increase [9,200 particles per cubic centimeter (cc)] relative UFP exposure was 1.04 [95% confidence interval (CI): 1.02, 1.06]. When comparing the fourth quartile of UFP exposure to the first quartile, the OR for PTB was 1.14 (95% CI: 1.08, 1.20), adjusting for maternal demographic characteristics, exposure to traffic-related air pollution, and airport-related noise. Conclusion: Our results suggest that emissions from aircraft play an etiologic role in PTBs, independent of noise and traffic-related air pollution exposures. These findings are of public health concern because UFP exposures downwind of airfields are common and may affect large, densely populated residential areas. https://doi.org/10.1289/EHP5732
Notch signaling licenses allergic airway inflammation by promoting Th2 cell lymph node egress
Authors: Irma Tindemans, Anne van Schoonhoven, Alex KleinJan, Marjolein J.W. de Bruijn, Melanie Lukkes, Menno van Nimwegen, Anouk van den Branden, Ingrid M. Bergen, Odilia B.J. Corneth, Wilfred F.J. van IJcken, Ralph Stadhouders, Rudi W. Hendriks
Journal: Journal of Clinical Investigation (2020)

Allergic asthma is mediated by Th2 responses to inhaled allergens. Although previous experiments indicated that Notch signaling activates expression of the key Th2 transcription factor Gata3, it remains controversial how Notch promotes allergic airway inflammation. Here we show that T cell-specific Notch deficiency in mice prevented house dust mite-driven eosinophilic airway inflammation and significantly reduced Th2 cytokine production, serum IgE levels, and airway hyperreactivity. However, transgenic Gata3 overexpression in Notch-deficient T cells only partially rescued this phenotype. We found that Notch signaling was not required for T cell proliferation or Th2 polarization. Instead, Notch-deficient in vitro-polarized Th2 cells showed reduced accumulation in the lungs upon in vivo transfer and allergen challenge, as Notch-deficient Th2 cells were retained in the lung-draining lymph nodes. Transcriptome analyses and sequential adoptive transfer experiments revealed that while Notch-deficient lymph node Th2 cells established competence for lung migration, they failed to upregulate sphingosine-1-phosphate receptor 1 (S1PR1) and its critical upstream transcriptional activator Krüppel-like factor 2 (KLF2). As this KLF2/S1PR1 axis represents the essential cell-intrinsic regulator of T cell lymph node egress, we conclude that the druggable Notch signaling pathway licenses the Th2 response in allergic airway inflammation via promoting lymph node egress.
Differential inflammasome activation predisposes to acute-on-chronic liver failure in human and experimental cirrhosis with and without previous decompensation
Authors: Sofia Monteiro, Josephine Grandt, Frank Erhard Uschner, Nina Kimer, Jan Lysgård Madsen, Robert Schierwagen, Sabine Klein, Christoph Welsch, Liliana Schäfer, Christian Jansen, Joan Claria, José Alcaraz-Quiles, Vicente Arroyo, Richard Moreau, Javier Fernandez, Flemming Bendtsen, Gautam Mehta, Lise Lotte Gluud, Søren Møller, Michael Praktiknjo, Jonel Trebicka
Journal: Gut (2020)

Objective Systemic inflammation predisposes acutely decompensated (AD) cirrhosis to the development of acute-on-chronic liver failure (ACLF). Supportive treatment can improve AD patients, becoming recompensated. Little is known about the outcome of patients recompensated after AD. We hypothesise that different inflammasome activation is involved in ACLF development in compensated and recompensated patients. Design 249 patients with cirrhosis, divided into compensated and recompensated (previous AD), were followed prospectively for fatal ACLF development. Two external cohorts (n=327) (recompensation, AD and ACLF) were included. Inflammasome-driving interleukins (ILs), IL-1α (caspase-4/11-dependent) and IL-1β (caspase-1-dependent), were measured. In rats, bile duct ligation-induced cirrhosis and lipopolysaccharide exposition were used to induce AD and subsequent recompensation. IL-1α and IL-1β levels and upstream/downstream gene expression were measured. Results Patients developing ACLF showed higher baseline levels of ILs. Recompensated patients and patients with detectable ILs had higher rates of ACLF development than compensated patients. Baseline CLIF-C (European Foundation for the study of chronic liver failure consortium) AD, albumin and IL-1α were independent predictors of ACLF development in compensated and CLIF-C AD and IL-1β in recompensated patients. Compensated rats showed higher IL-1α gene expression and recompensated rats higher IL-1β levels with higher hepatic gene expression. Higher IL-1β detection rates in recompensated patients developing ACLF and higher IL-1α and IL-1β detection rates in patients with ACLF were confirmed in the two external cohorts. Conclusion Previous AD is an important risk factor for fatal ACLF development and possibly linked with inflammasome activation. Animal models confirmed the results showing a link between ACLF development and IL-1α in compensated cirrhosis and IL-1β in recompensated cirrhosis.
It’s not all about muscle: fibroadipogenic progenitors contribute to facioscapulohumeral muscular dystrophy
Authors: Carlo Serra, Kathryn R. Wagner
Journal: Journal of Clinical Investigation (2020)

Facioscapulohumeral muscular dystrophy (FSHD) results from expression of the full-length double homeobox 4 (DUX4-FL) retrogene in skeletal muscle. However, even in cases of severe FSHD the presence of DUX4 is barely detectable. In this issue of the JCI, Bosnakovski et al. used an inducible, muscle-specific human DUX4 to reproduce the low-level, sporadic DUX4 expression of human FSHD muscle as well the myopathology seen in human FSHD disease. Notably, dysregulated fibroadipogenic progenitors accumulated in affected muscles, thus providing a mechanism for the replacement of muscle by fibrosis and fat.
Thermosensitive hydrogels as sustained drug delivery system for CTLA-4 checkpoint blocking antibodies
Authors: Chih Kit Chung, Marieke F. Fransen, Koen van der Maaden, Yaima Campos, Jomarien García-Couce, Dana Kralisch, Alan Chan, Ferry Ossendorp, Luis J. Cruz
Journal: Journal of Controlled Release (2020)

Thermosensitive poloxamer 407 (P407) hydrogels were evaluated as slow release system for optimizing CTLA-4 therapy. Slow release reduces systemic antibody levels and potentially mitigates the side effects of CTLA-4 therapy. The 25% P407 hydrogel is injectable at room temperature and depots are established quickly after subcutaneous injection. Scanning electron microscopy revealed the porous structure of the hydrogel, average pore surface was 1335 μm2. Release studies were optimized using the human IgG antibody. IgG was easily incorporated in the hydrogel by simple mixing and no antibodies were lost during preparation. In vitro, hydrogels showed low burst release within the first 24 h. Total IgG load was gradually released within 120 h. In vitro cytotoxicity assays showed that P407 is not cytotoxic and induces no immune activation by itself. In vivo, P407 hydrogels significantly reduced serum IgG levels, were biocompatible and were broken down 1 week after injection. Finally, local hydrogel delivery of anti-CTLA-4 antibodies near established tumors effectively slowed down tumor growth, whilst significantly reduced serum anti-CTLA-4 levels. Altogether, P407 hydrogels represent promising delivery systems for the optimization of CTLA-4 blocking therapy.
Abstract 10333: Carotid Artery Echolucency, Texture Features, and Incident Cardiovascular Disease Events: the Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Carol Mitchell, Claudia E Korcarz, Adam D Gepner, Rebecca Nye, Rebekah L Young, Mika Matsuzaki, Wendy S Post, Joel D Kaufman, Robyn L McClelland, James H Stein
Journal: Circulation (2018)

Background: Grayscale analysis of ultrasound images can characterize arterial wall structure and tissue composition. We hypothesized that measures of carotid artery grayscale texture were associate...
Medicare Part D and Insulin Affordability — The Devil Is in the Details
Authors: Stacie B. Dusetzina, Haiden A. Huskamp, Laura M. Keohane, Nancy L. Keating
Journal: New England Journal of Medicine (2020)

Millions of Americans rely on insulin, and reports about cost-related underuse and subsequent deaths, primarily among uninsured or underinsured people, have proliferated in the popular press. But affordability of insulin may also be a concern for Medicare beneficiaries.
Admission to hospital in the UK at a weekend does not influence the prognosis of adults with community-acquired pneumonia
Authors: Hannah Lawrence, Tricia M McKeever, Wei Shen Lim
Journal: Thorax (2020)

Outcomes for adults with community-acquired pneumonia (CAP) admitted to hospital at the weekend were compared with those admitted during weekdays using data from the British Thoracic Society national CAP audits. Of 31 400 cases, 40.7% were weekend admissions; these patients were older (mean age 72 vs 71.3 years, p=0.001) and more likely to have high severity CAP (28.9% vs 27.1%, p trend 0.003) but had slightly lower adjusted 30-day inpatient mortality (aOR 0.94 95% CI 0.88 to 1.01) compared with those admitted during weekdays. More patients in the weekend group received antibiotics within 4 hours of admission (70.3% vs 68.7%, aOR 1.07 95% CI 1.01 to 1.12). We did not observe increased mortality for adults admitted at the weekend with CAP.
The Role of Physicians in Addressing Social Determinants of Health
Authors: Nason Maani, Sandro Galea
Journal: JAMA (2020)

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Xenon blunts NF-κB/NLRP3 inflammasome activation and improves acute onset of accelerated and severe lupus nephritis in mice
Authors: Shin-Ruen Yang, Kuo-Feng Hua, Lichieh Julie Chu, Yeu-Kuang Hwu, Shun-Min Yang, Chung-Yao Wu, Tsai-Jung Lin, Jui-Chun Weng, Hailin Zhao, Wan-Han Hsu, Feng-Cheng Liu, Wen-Jinn Liaw, Daqing Ma, Shuk-Man Ka, Ann Chen
Journal: Kidney International (2020)