tbuckley/cabot-search huggingface dataset:
USF1 defect drives p53 degradation during <i>Helicobacter pylori</i> infection and accelerates gastric carcinogenesis
Authors: Lionel Costa, Sébastien Corre, Valérie Michel, Krysten Le Luel, Julien Fernandes, Jason Ziveri, Gregory Jouvion, Anne Danckaert, Nicolas Mouchet, David Da Silva Barreira, Javier Torres, Margarita Camorlinga, Mario Milco D'Elios, Laurence Fiette, Hilde De Reuse, Marie-Dominique Galibert, Eliette Touati
Journal: Gut (2019)

Helicobacter pylori (Hp) is a major risk factor for gastric cancer (GC). Hp promotes DNA damage and proteasomal degradation of p53, the guardian of genome stability. Hp reduces the expression of the transcription factor USF1 shown to stabilise p53 in response to genotoxic stress. We investigated whether Hp-mediated USF1 deregulation impacts p53-response and consequently genetic instability. We also explored in vivo the role of USF1 in gastric carcinogenesis.Human gastric epithelial cell lines were infected with Hp7.13, exposed or not to a DNA-damaging agent camptothecin (CPT), to mimic a genetic instability context. We quantified the expression of USF1, p53 and their target genes, we determined their subcellular localisation by immunofluorescence and examined USF1/p53 interaction. Usf1-/- and INS-GAS mice were used to strengthen the findings in vivo and patient data examined for clinical relevance.In vivo we revealed the dominant role of USF1 in protecting gastric cells against Hp-induced carcinogenesis and its impact on p53 levels. In vitro, Hp delocalises USF1 into foci close to cell membranes. Hp prevents USF1/p53 nuclear built up and relocates these complexes in the cytoplasm, thereby impairing their transcriptional function. Hp also inhibits CPT-induced USF1/p53 nuclear complexes, exacerbating CPT-dependent DNA damaging effects.Our data reveal that the depletion of USF1 and its de-localisation in the vicinity of cell membranes are essential events associated to the genotoxic activity of Hp infection, thus promoting gastric carcinogenesis. These findings are also of clinical relevance, supporting USF1 expression as a potential marker of GC susceptibility.
Towards standardisation: comparison of five whole genome sequencing (WGS) analysis pipelines for detection of epidemiologically linked tuberculosis cases
Authors: Rana Jajou, Thomas A Kohl, Timothy Walker, Anders Norman, Daniela Maria Cirillo, Elisa Tagliani, Stefan Niemann, Albert de Neeling, Troels Lillebaek, Richard M Anthony, Dick van Soolingen
Journal: Eurosurveillance (2019)

Background Whole genome sequencing (WGS) is a reliable tool for studying tuberculosis (TB) transmission. WGS data are usually processed by custom-built analysis pipelines with little standardisation between them. Aim To compare the impact of variability of several WGS analysis pipelines used internationally to detect epidemiologically linked TB cases. Methods From the Netherlands, 535 Mycobacterium tuberculosis complex (MTBC) strains from 2016 were included. Epidemiological information obtained from municipal health services was available for all mycobacterial interspersed repeat unit-variable number of tandem repeat (MIRU-VNTR) clustered cases. WGS data was analysed using five different pipelines: one core genome multilocus sequence typing (cgMLST) approach and four single nucleotide polymorphism (SNP)-based pipelines developed in Oxford, United Kingdom; Borstel, Germany; Bilthoven, the Netherlands and Copenhagen, Denmark. WGS clusters were defined using a maximum pairwise distance of 12 SNPs/alleles. Results The cgMLST approach and Oxford pipeline clustered all epidemiologically linked cases, however, in the other three SNP-based pipelines one epidemiological link was missed due to insufficient coverage. In general, the genetic distances varied between pipelines, reflecting different clustering rates: the cgMLST approach clustered 92 cases, followed by 84, 83, 83 and 82 cases in the SNP-based pipelines from Copenhagen, Oxford, Borstel and Bilthoven respectively. Conclusion Concordance in ruling out epidemiological links was high between pipelines, which is an important step in the international validation of WGS data analysis. To increase accuracy in identifying TB transmission clusters, standardisation of crucial WGS criteria and creation of a reference database of representative MTBC sequences would be advisable.
Tim-3 Hampers Tumor Surveillance of Liver-Resident and Conventional NK Cells by Disrupting PI3K Signaling
Authors: Siyu Tan, Yong Xu, Zehua Wang, Tixiao Wang, Xianhong Du, Xiaojia Song, Xiaowei Guo, Jiali Peng, Jie Zhang, Yan Liang, Jinghui Lu, Jun Peng, Chengjiang Gao, Zhuanchang Wu, Chunyang Li, Nailin Li, Lifen Gao, Xiaohong Liang, Chunhong Ma
Journal: Cancer Research (2019)

Natural killer (NK) cells are enriched within the liver. Apart from conventional NK (cNK) cells, recent studies identified a liver-resident NK (LrNK) subset, which constitutes about half of hepatic NK cells and exhibits distinct developmental, phenotypic, and functional features. However, it remains unclear whether and how LrNK cells, as well as cNK cells, participate in the development of hepatocellular carcinoma (HCC) individually. Here, we report that both LrNK and cNK cells are significantly decreased in HCC. The T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) was significantly upregulated in both tumor-infiltrating LrNK and cNK cells and suppressed their cytokine secretion and cytotoxic activity. Mechanistically, phosphatidylserine (PtdSer) engagement promoted phosphorylation of Tim-3, which then competed with PI3K p110 to bind p85, inhibiting downstream Akt/mTORC1 signaling and resulting in malfunctioning of both NK-cell subsets. Tim-3 blockade retarded HCC growth in a NK-cell-dependent manner. These studies for the first time report the presence and dysfunction of LrNK cells in HCC and show that Tim-3-mediated PI3K/mTORC1 interference is responsible for the dysfunction of both tumor-infiltrating cNK and LrNK cells, providing a new strategy for immune checkpoint-based targeting. SIGNIFICANCE: Tim-3 enhances hepatocellular carcinoma growth by blocking natural killer cell function.
Can Quantitative CMR Tissue Characterization Adequately Identify Cardiotoxicity During Chemotherapy?
Authors: Mustafa A. Altaha, Mark Nolan, Thomas H. Marwick, Emily Somerset, Christian Houbois, Eitan Amir, Paul Yip, Kim A. Connelly, Maria Michalowska, Marshall S. Sussman, Bernd J. Wintersperger, Paaladinesh Thavendiranathan
Journal: JACC. Cardiovascular imaging (2019)
Single-Cell RNA-Seq Identifies Potentially Pathogenic B Cell Populations That Uniquely Circulate in Patients with Chronic Gvhd
Authors: Jonathan C Poe, Dadong Zhang, Jichun Xie, Rachel A. DiCioccio, Xiaodi Qin, Jiyuan Fang, Vincent T. Ho, Jeremy J. Rose, Steven Z. Pavletic, Frances T. Hakim, Wei Jia, Amy N. Suthers, Mitchell E. Horwitz, David A. Rizzieri, William C. McManigle, Nelson J. Chao, Kouros Owzar, Stefanie Sarantopoulos
Journal: Blood (2019)
Bushfires: Australia issues health warnings as Sydney air quality plummets
Authors: Bianca Nogrady
Journal: BMJ (2019)

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Large bushfires have shrouded Australia’s east coast in dense smoke, prompting health authorities to issue warnings as Sydney’s air quality index exceeded hazardous levels by a factor of 10.1

The number of people across New South Wales presenting to hospital emergency departments with respiratory problems increased by around 25% above the usual weekly average for the first week of December, and ambulance callouts are up by around 30%, says a report from NSW Health, the state health department.2

Sydney is in one of the worst affected areas. On 10 December the city’s air quality index—a composite score of levels of ozone, carbon monoxide, …
A novel ImmunoScore, based on clinical and blood biomarkers, as prognostic model for immunotherapy in NSCLC
Authors: G. Viscardi, F. Sparano, R. Di Liello, G. Alonso Casal, R. Borras Ferreres, G. Bruixola, V. Gambardella, N. Zanaletti, M.L. Iacovino, C. Mlla De Corte, F. Papaccio, M. Fasano, F. Ciardiello, A. Cervantes, F. Morgillo, P. Martin Martorell, M. AInsa Molla
Journal: Annals of Oncology (2019)
Interleukin 1 receptor antagonist (<i>IL1RN</i>) gene variants predict radiographic severity of knee osteoarthritis and risk of incident disease
Authors: Mukundan Attur, Hua Zhou, Johathan Samuels, Svetlana Krasnokutsky, Michelle Yau, Jose U Scher, Michael Doherty, Anthony G Wilson, Jenny Bencardino, Marc Hochberg, Joanne M Jordan, Braxton Mitchell, Virginia B Kraus, Steven B Abramson
Journal: Annals of the Rheumatic Diseases (2019)

Objective In these studies, we examined the association of single nucleotide polymorphisms (SNPs) of the IL1RN gene with radiographic severity of symptomatic knee osteoarthritis (SKOA) and the risk of incident OA. We also explored these genetic polymorphisms in patients with new onset rheumatoid arthritis (RA). Methods Over 1000 subjects who met American College of Rheumatology criteria for tibiofemoral OA were selected from three independent, National Institute of Health (NIH)-funded cohorts. CTA and TTG haplotypes formed from three SNPs of the IL1RN gene (rs419598, rs315952, rs9005) were assessed for association with radiographic severity, and risk for incident radiographic OA (rOA) in a nested case–control cohort. These IL1RN haplotypes were also assessed for association with disease activity (DAS28) and plasma inflammatory markers in patients with RA. Results Carriage of the IL1RN TTG haplotype was associated with increased odds of more severe rOA compared with age-matched, sex-matched and body mass index-matched individuals. Examination of the osteoarthritis initiative Incidence Subcohort demonstrated that carriage of the TTG haplotype was associated with 4.1-fold (p=0.001) increased odds of incident rOA. Plasma IL-1Ra levels were lower in TTG carriers, while chondrocytes from TTG carriers exhibited decreased secretion of IL-1Ra. In patients with RA, the TTG haplotype was associated with increased DAS28, decreased plasma IL-1Ra and elevations of plasma inflammatory markers (hsCRP, interleukin 6 (IL-6)). Conclusion Carriage of the IL1RN TTG haplotype is associated with more severe rOA, increased risk for incident OA, and increased evidence of inflammation in RA. These data suggest that the IL1RN TTG risk haplotype, associated with decreased IL-1Ra plasma levels, impairs endogenous ‘anti-inflammatory’ mechanisms.
Metabolic Imaging Using Hyperpolarized Pyruvate–Lactate Exchange Assesses Response or Resistance to the EGFR Inhibitor Cetuximab in Patient-Derived HNSCC Xenografts
Authors: Lionel Mignion, Stefania Acciardo, Florian Gourgue, Nicolas Joudiou, Xavier Caignet, Rose-Marie Goebbels, Cyril Corbet, Olivier Feron, Caroline Bouzin, Patrice D. Cani, Jean-Pascal Machiels, Sandra Schmitz, Bénédicte F. Jordan
Journal: Clinical Cancer Research (2019)

Optimal head and neck squamous cell carcinoma (HNSCC) patient selection for anti-EGFR-based therapy remains an unmet need since only a minority of patients derive long-term benefit from cetuximab treatment. We assessed the ability of state-of-the-art noninvasive in vivo metabolic imaging to probe metabolic shift in cetuximab-sensitive and -resistant HNSCC patient-derived tumor xenografts (PDTXs).Three models selected based on their known sensitivity to cetuximab in patients (cetuximab-sensitive or acquired-resistant HNC007 PDTXs, cetuximab-naïve UCLHN4 PDTXs, and cetuximab-resistant HNC010 PDTXs) were inoculated in athymic nude mice.Cetuximab induced tumor size stabilization in mice for 4 weeks in cetuximab-sensitive and -naïve models treated with weekly injections (30 mg/kg) of cetuximab. Hyperpolarized 13C-pyruvate-13C-lactate exchange was significantly decreased in vivo in cetuximab-sensitive xenograft models 8 days after treatment initiation, whereas it was not modified in cetuximab-resistant xenografts. Ex vivo analysis of sensitive tumors resected at day 8 after treatment highlighted specific metabolic changes, likely to participate in the decrease in the lactate to pyruvate ratio in vivo. Diffusion MRI showed a decrease in tumor cellularity in the HNC007-sensitive tumors, but failed to show sensitivity to cetuximab in the UCLHN4 model.This study constitutes the first in vivo demonstration of cetuximab-induced metabolic changes in cetuximab-sensitive HNSCC PDTXs that were not present in resistant tumors. Using metabolic imaging, we were able to identify hyperpolarized 13C-pyruvate as a potential marker for response and resistance to the EGFR inhibitor in HNSCC.
The High Burden of Sexually Transmitted Infections in Persons Initiating Preexposure Prophylaxis—Challenge or Opportunity?
Authors: Roger Chou
Journal: JAMA Network Open (2019)

Jason J. Ong, PhD, MBBS; Rachel C. Baggaley, MSc, MBBS; Teodora E. Wi, MD; Joseph D. Tucker, PhD, MD; Hongyun Fu, PhD; M. Kumi Smith, PhD; Sabrina Rafael, MSc; Vanessa Anglade, MSc; Jane Falconer, MA; Richard Ofori-Asenso, PhD; Fern Terris-Prestholt, PhD; Ioannis Hodges-Mameletzis, DPhil; Philippe Mayaud, MD
Corrigendum to “Retention of stemness and vasculogenic potential of human umbilical cord blood stem cells after repeated expansions on PES-nanofiber matrices” [Biomaterials 35 (2014) 8566–8575]
Authors: Matthew Joseph, Manjusri Das, Suman Kanji, Jingwei Lu, Reeva Aggarwal, Debanjan Chakraborty, Chandrani Sarkar, Hongmei Yu, Hai-Quan Mao, Sujit Basu, Vincent J. Pompili, Hiranmoy Das
Journal: Biomaterials (2019)
Tenosynovitis Due to <i>Mycobacterium avium</i> Complex
Authors: Lucas Kreutz-Rodrigues, Karim Bakri
Journal: New England Journal of Medicine (2019)

A 51-year-old right-handed man presented with swelling in the left wrist. MRI showed rice bodies and culture confirmed invasive mycobacterial tenosynovitis due to Mycobacterium avium complex.
The selfishly selfless placenta
Authors: Nermi L. Parrow, Robert E. Fleming
Journal: Journal of Clinical Investigation (2019)

Although iron deficiency continues to pose a problem for pregnant women and fetal development, an incomplete understanding of placental adaptation to limited iron availability has hindered efforts to identify optimal supplementation strategies. In this issue of the JCI, Sangkhae et al. used mouse models and human placentas to explore maternal, placental, and fetal responses to alterations in iron status during pregnancy. The authors identified molecular mechanisms that limit placental ability to upregulate iron transport in the setting of severe iron deficiency and explored a potential marker of placental maladaptation.
Standardisation of cardiopulmonary exercise testing in chronic lung diseases: summary of key findings from the ERS task force
Authors: Thomas Radtke, Ioannis Vogiatzis, Don S. Urquhart, Pierantonio Laveneziana, Richard Casaburi, Helge Hebestreit
Journal: European Respiratory Journal (2019)

<b>The new ERS statement facilitates standardisation of conducting, reporting and interpreting cardiopulmonary exercise tests in chronic lung diseases. The conclusions are especially valuable for multicentre comparisons and for establishing global reference data.</b>http://bit.ly/32Y0eO0
Development and Validation of a Machine Learning Model to Aid Discharge Processes for Inpatient Surgical Care
Authors: Kyan C. Safavi, Taghi Khaniyev, Martin Copenhaver, Mark Seelen, Ana Cecilia Zenteno Langle, Jonathan Zanger, Bethany Daily, Retsef Levi, Peter Dunn
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Inpatient overcrowding is associated with delays in care, including the deferral of surgical care until beds are available to accommodate postoperative patients. Timely patient discharge is critical to address inpatient overcrowding and requires coordination among surgeons, nurses, case managers, and others. This is difficult to achieve without early identification and systemwide transparency of discharge candidates and their respective barriers to discharge. <h3>Objective</h3> To validate the performance of a clinically interpretable feedforward neural network model that could improve the discharge process by predicting which patients would be discharged within 24 hours and their clinical and nonclinical barriers. <h3>Design, Setting, and Participants</h3> This prognostic study included adult patients discharged from inpatient surgical care from May 1, 2016, to August 31, 2017, at a quaternary care teaching hospital. Model performance was assessed with standard cross-validation techniques. The model's performance was compared with a baseline model using historical procedure median length of stay to predict discharges. In prospective cohort analysis, the feedforward neural network model was used to make predictions on general surgical care floors with 63 beds. If patients were not discharged when predicted, the causes of delay were recorded. <h3>Main Outcomes and Measures</h3> The primary outcome was the out-of-sample area under the receiver operating characteristic curve of the model. Secondary outcomes included the causes of discharge delay and the number of avoidable bed-days. <h3>Results</h3> The model was trained on 15 201 patients (median [interquartile range] age, 60 [46-70] years; 7623 [50.1%] men) discharged from inpatient surgical care. The estimated out-of-sample area under the receiver operating characteristic curve of the model was 0.840 (SD, 0.008; 95% CI, 0.839-0.844). Compared with the baseline model, the neural network model had higher sensitivity (52.5% vs 56.6%) and specificity (51.7% vs 82.6%). The neural network model identified 65 barriers to discharge. In the prospective study of 605 patients, causes of delays included clinical barriers (41 patients [30.1%]), variation in clinical practice (30 patients [22.1%]), and nonclinical reasons (65 patients [47.8%]). Summing patients who were not discharged owing to variation in clinical practice and nonclinical reasons, 128 bed-days, or 1.2 beds per day, were classified as avoidable. <h3>Conclusions and Relevance</h3> This cohort study found that a neural network model could predict daily inpatient surgical care discharges and their barriers. The model identified systemic causes of discharge delays. Such models should be studied for their ability to increase the timeliness of discharges.
Human Health Benefits from Fish Consumption vs. Risks from Inhalation Exposures Associated with Contaminated Sediment Remediation: Dredging of the Hudson River
Authors: Jacob Kvasnicka, Katerina S. Stylianou, Vy K. Nguyen, Lei Huang, Weihsueh A. Chiu, G. Allen Burton, Jeremy Semrau, Olivier Jolliet
Journal: Environmental Health Perspectives (2019)

Billions of dollars are spent on environmental dredging (ED) to remediate contaminated sediments, with one goal being reduced human health risks. However, ED may increase health risks in unanticipated ways, thus potentially reducing net benefits.To assess the ways that ED may increase health risks in unanticipated ways, thus potentially reducing net benefits, we quantitatively assessed a subset of population health benefits and risks of ED, using the 2009-2015 remediation of the Hudson River Polychlorinated Biphenyls (PCBs) Superfund Site as a case study. Three remediation scenarios were evaluated: No Action (NA), Source Control (SC), and ED.We quantified health benefits for each scenario from reduced PCB levels in Hudson River fish, and health risks from ED operations due to increased inhalation exposures to PCBs and fine particulate matter (PM2.5), using disability-adjusted life years (DALYs) as a common metric. Occupational health risks were also considered in a separate sensitivity analysis. Estimates of population-level benefits and risks included Monte Carlo simulation-based uncertainty analysis.Under NA, fish consumption would result in an estimated health burden of 112 DALYs, and ED would lead to a reduction of 15 DALYs in excess of SC. ED operations were estimated to induce a total burden of 33 DALYs, dominated by PM2.5 impacts from rail transport emissions (32 DALYs). Including uncertainty, the net health benefit of ED ranged from -138 to +1,326 avoided DALYs (90% confidence), with a median of -11 avoided DALYs.For the considered impacts, ED in the Hudson River might not have led to an overall net positive human health impact. The benefits and risks of ED, however, have different degrees of uncertainty and involve different populations. Reducing long-distance transport of dredged sediment is a priority. This comparative approach could be used prospectively to better determine trade-offs involved in different remediation scenarios and to improve remediation design to maximize benefits while minimizing risks. https://doi.org/10.1289/EHP5034.
Parallel Seed Color Adaptation during Multiple Domestication Attempts of an Ancient New World Grain
Authors: Markus G Stetter, Mireia Vidal-Villarejo, Karl J Schmid
Journal: Molecular Biology and Evolution (2019)

Thousands of plants have been selected as crops; yet, only a few are fully domesticated. The lack of adaptation to agroecological environments of many crop plants with few characteristic domestication traits potentially has genetic causes. Here, we investigate the incomplete domestication of an ancient grain from the Americas, amaranth. Although three grain amaranth species have been cultivated as crop for millennia, all three lack key domestication traits. We sequenced 121 crop and wild individuals to investigate the genomic signature of repeated incomplete adaptation. Our analysis shows that grain amaranth has been domesticated three times from a single wild ancestor. One trait that has been selected during domestication in all three grain species is the seed color, which changed from dark seeds to white seeds. We were able to map the genetic control of the seed color adaptation to two genomic regions on chromosomes 3 and 9, employing three independent mapping populations. Within the locus on chromosome 9, we identify an MYB-like transcription factor gene, a known regulator for seed color variation in other plant species. We identify a soft selective sweep in this genomic region in one of the crop species but not in the other two species. The demographic analysis of wild and domesticated amaranths revealed a population bottleneck predating the domestication of grain amaranth. Our results indicate that a reduced level of ancestral genetic variation did not prevent the selection of traits with a simple genetic architecture but may have limited the adaptation of complex domestication traits.