tbuckley/cabot-search huggingface dataset:
Association of Copy Number Variation Signature and Survival in Patients With Serous Ovarian Cancer
Authors: Ryon P. Graf, Ramez Eskander, Leo Brueggeman, Dwayne G. Stupack
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Tailoring therapeutic regimens to individual patients with ovarian cancer is informed by severity of disease using a variety of clinicopathologic indicators. Although DNA repair variations are increasingly used for therapy selection in ovarian cancer, molecular features are not widely used for general assessment of patient prognosis and disease severity. <h3>Objective</h3> To distill a highly dynamic characteristic, signature of copy number variations (CNV), into a risk score that could be easily validated analytically or repurposed for use given existing US Food and Drug Administration (FDA)–approved multigene assays. <h3>Design, Setting, and Participants</h3> This genetic association study used the Cancer Genome Atlas Ovarian Cancer database to assess for genome-wide survival associations agnostic to gene function. Regions enriched for significant associations were compared to associations from scrambled data. CNV associations were condensed into a risk score, which was internally validated using bootstrapping. The participants were patients with serous ovarian cancer (stages I-IV) diagnosed from 1992 to 2013. Statistical analysis was performed from April to July 2020. <h3>Main Outcomes and Measures</h3> Overall survival (OS). <h3>Results</h3> Among 564 patients with serous ovarian cancer, the mean (SD) age was 59.7 (11.5) years; 34 (6%) identified as Black or African American. A total of 13 genome regions, comprising 14 alterations, were identified as significantly risk associated. Composite risk score was independent of total CNV burden, total mutational burden,<i>BRCA</i>status, and open-source genome-wide DNA repair deficiency signatures. Binned terciles yielded high-, standard-, and low-risk groups with respective median OS estimates of 2.9 (95% CI, 2.3-3.2) years, 4.1 (95% CI, 3.7-4.8) years, and 5.7 (95% CI, 4.7-7.4) years, respectively (<i>P</i> &lt; .001). Associated 5-year survival estimates in each tercile were 15% (95% CI, 10%-22%), 36% (95% CI, 29%-46%), and 53% (95% CI, 45%-62%). The risk score had more discriminatory ability to prognosticate OS than age, clinical stage, grade, and race combined, and was strongly additive to significant clinical features (<i>P</i> &lt; .001). Simulated adaptation of FDA-approved assays showed similar performance. Gene ontology analyses of identified regions showed an enrichment for regulatory miRNAs and protein kinase regulators. <h3>Conclusions and Relevance</h3> This study found that a CNV-based risk score is independent to and stronger than current or near-future ovarian cancer genomic biomarkers to prognosticate OS. CNV regions identified were not strongly associated with canonical ovarian cancer biological pathways, identifying candidates for future mechanistic investigations. External validation of the CNV risk score, especially in concert with more extensive clinical features, could be pursued via existing FDA-approved assays.
<i>Fusobacterium Nucleatum</i> Promotes the Development of Colorectal Cancer by Activating a Cytochrome P450/Epoxyoctadecenoic Acid Axis via TLR4/Keap1/NRF2 Signaling
Authors: Cheng Kong, Xuebing Yan, Yefei Zhu, Huiyuan Zhu, Ying Luo, Peipei Liu, Sylvain Ferrandon, Matthew F. Kalady, Renyuan Gao, Jide He, Fang Yin, Xiao Qu, Jiayi Zheng, Yaohui Gao, Qing Wei, Yanlei Ma, Jun-Yan Liu, Huanlong Qin
Journal: Cancer Research (2021)

Abstract Emerging research has revealed regulation of colorectal cancer metabolism by bacteria. Fusobacterium nucleatum (Fn) plays a crucial role in the development of colorectal cancer, however, whether Fn infection modifies metabolism in patients with colorectal cancer remains unknown. Here, LC-MS/MS-based lipidomics identified the upregulation of cytochrome P450 monooxygenases, primarily CYP2J2, and their mediated product 12,13-EpOME in patients with colorectal cancer tumors and mouse models, which increased the invasive and migratory ability of colorectal cancer cells in vivo and in vitro by regulating the epithelial–mesenchymal transition (EMT). Metagenomic sequencing indicated a positive correlation between increased levels of fecal Fn and serum 12,13-EpOME in patients with colorectal cancer. High levels of CYP2J2 in tumor tissues also correlated with high Fn levels and worse overall survival in patients with stage III/IV colorectal cancer. Moreover, Fn was found to activate TLR4/AKT signaling, downregulating Keap1 and increasing NRF2 to promote transcription of CYP2J2. Collectively, these data identify that Fn promotes EMT and metastasis in colorectal cancer by activating a TLR4/Keap1/NRF2 axis to increase CYP2J2 and 12,13-EpOME, which could serve as clinical biomarkers and therapeutic targets for Fn-infected patients with colorectal cancer. Significance: This study uncovers a mechanism by which Fusobacterium nucleatum regulates colorectal cancer metabolism to drive metastasis, suggesting the potential biomarker and therapeutic utility of the CYP2J2/12,13–EpOME axis in Fn-infected patients.
A case of acute radiation syndrome from the dermatological aspect
Authors: T. Hoashi, H. Okochi, T. Kadono, K. Tamaki, M. Nishida, S. Futami, K. Maekawa
Journal: British Journal of Dermatology (2008)

Accidental whole‐body overexposure of radiation occurs very rarely. Radiation exposure causes DNA breaks in the cells and shows various clinical features, which are time dependent, dose dependent and tissue dependent. Neutron rays are more destructive than gamma rays but their actual effect on humans have been under‐reported. We observed the time‐dependent and the dose‐dependent dermatological changes in a patient who was severely irradiated by neutron and gamma rays, with the aim of clarifying the clinicopathological features of severely irradiated skin. The detection of DNA breaks in keratinocytes was performed by the terminal deoxynucleotidyl transferase‐mediated deoxyuridine triphosphate nick end labelling technique. The degenerative changes of the skin and the re‐epithelialization varied in a time dependent and dose dependent manner. DNA breaks were significantly higher in irradiated keratinocytes. Neutron rays caused depth‐dependent degeneration of the skin. Evaluation of DNA breaks in the skin cells might be a clue to estimate local dosimetry.
Efficacy and safety of adalimumab in paediatric patients with moderate-to-severe ulcerative colitis (ENVISION I): a randomised, controlled, phase 3 study
Authors: Nicholas M Croft, William A Faubion, Subra Kugathasan, Jaroslaw Kierkus, Frank M Ruemmele, Toshiaki Shimizu, Nael M Mostafa, Mary Venetucci, Tricia Finney-Hayward, Yuri Sanchez Gonzalez, Mareike Bereswill, Andreas Lazar, Dan Turner
Journal: The Lancet. Gastroenterology & hepatology (2021)
Improving Health Equity and Reducing Disparities in Pediatric and Adolescent/Young Adult Oncology: In Support of Clinical Practice Guidelines
Authors: Justine M. Kahn, Melissa Beauchemin
Journal: Journal of the National Comprehensive Cancer Network (2021)

Despite extraordinary strides in cancer therapy over the past 30 years, racial/ethnic, socioeconomic, and age-related survival disparities persist. Hodgkin lymphoma offers an excellent paradigm to understand these disparities because successful approaches are well established in both the up-front and relapsed treatment settings. The following review, which accompanies the 2021 NCCN Guidelines for Pediatric Hodgkin Lymphoma, suggests that systemic inequities in cancer care disproportionately affect minority and low-income children, adolescents, and young adults, and directly contribute to observed disparities in cancer-related outcomes. It proposes that the first step toward reducing disparities is large-scale dissemination of guidelines, because equity is best achieved when treatment approaches are clear, comprehensive, and standardized across all clinical practice settings.
Anterior thalamic dysfunction underlies cognitive deficits in a subset of neuropsychiatric disease models
Authors: Dheeraj S. Roy, Ying Zhang, Tomomi Aida, Soonwook Choi, Qian Chen, Yuanyuan Hou, Nicholas E. Lea, Keith M. Skaggs, Juliana C. Quay, Min Liew, Hannah Maisano, Vinh Le, Carter Jones, Jie Xu, Dong Kong, Heather A. Sullivan, Arpiar Saunders, Steven A. McCarroll, Ian R. Wickersham, Guoping Feng
Journal: Neuron (2021)
Integrated genomic-metabolic classification of acute myeloid leukemia defines a subgroup with NPM1 and cohesin/DNA damage mutations
Authors: Giorgia Simonetti, Carlo Mengucci, Antonella Padella, Eugenio Fonzi, Gianfranco Picone, Claudio Delpino, Jacopo Nanni, Rossella De Tommaso, Eugenia Franchini, Cristina Papayannidis, Giovanni Marconi, Martina Pazzaglia, Margherita Perricone, Emanuela Scarpi, Maria Chiara Fontana, Samantha Bruno, Michela Tebaldi, Anna Ferrari, Maria Teresa Bochicchio, Andrea Ghelli Luserna Di Rorà, Martina Ghetti, Roberta Napolitano, Annalisa Astolfi, Carmen Baldazzi, Viviana Guadagnuolo, Emanuela Ottaviani, Ilaria Iacobucci, Michele Cavo, Gastone Castellani, Torsten Haferlach, Daniel Remondini, Francesco Capozzi, Giovanni Martinelli
Journal: Leukemia (2021)

Although targeting of cell metabolism is a promising therapeutic strategy in acute myeloid leukemia (AML), metabolic dependencies are largely unexplored. We aimed to classify AML patients based on their metabolic landscape and map connections between metabolic and genomic profiles. Combined serum and urine metabolomics improved AML characterization compared with individual biofluid analysis. At intracellular level, AML displayed dysregulated amino acid, nucleotide, lipid, and bioenergetic metabolism. The integration of intracellular and biofluid metabolomics provided a map of alterations in the metabolism of polyamine, purine, keton bodies and polyunsaturated fatty acids and tricarboxylic acid cycle. The intracellular metabolome distinguished three AML clusters, correlating with distinct genomic profiles: NPM1-mutated(mut), chromatin/spliceosome-mut and TP53-mut/aneuploid AML that were confirmed by biofluid analysis. Interestingly, integrated genomic-metabolic profiles defined two subgroups of NPM1-mut AML. One was enriched for mutations in cohesin/DNA damage-related genes (NPM1/cohesin-mut AML) and showed increased serum choline + trimethylamine-N-oxide and leucine, higher mutation load, transcriptomic signatures of reduced inflammatory status and better ex-vivo response to EGFR and MET inhibition. The transcriptional differences of enzyme-encoding genes between NPM1/cohesin-mut and NPM1-mut allowed in silico modeling of intracellular metabolic perturbations. This approach predicted alterations in NAD and purine metabolism in NPM1/cohesin-mut AML that suggest potential vulnerabilities, worthy of being therapeutically explored.
Inspiratory Effort and Lung Mechanics in Spontaneously Breathing Patients with Acute Respiratory Failure due to COVID-19: A Matched Control Study
Authors: Roberto Tonelli, Stefano Busani, Luca Tabbì, Riccardo Fantini, Ivana Castaniere, Emanuela Biagioni, Cristina Mussini, Massimo Girardis, Enrico Clini, Alessandro Marchioni
Journal: American Journal of Respiratory and Critical Care Medicine (2021)
Cadmium Exposure and Coronary Artery Atherosclerosis: A Cross-Sectional Population-Based Study of Swedish Middle-Aged Adults
Authors: Lars Barregard, Gerd Sallsten, Florencia Harari, Eva M. Andersson, Niklas Forsgard, Ola Hjelmgren, Oskar Angerås, Erika Fagman, Margaretha Persson, Thomas Lundh, Yan Borné, Björn Fagerberg, Gunnar Engström, Göran Bergström
Journal: Environmental Health Perspectives (2021)

The general population is ubiquitously exposed to the toxic metal cadmium through the diet and smoking. Cadmium exposure is associated with increased morbidity and mortality in myocardial infarction and stroke. Atherosclerosis is the main underlying mechanism of myocardial infarction. However, associations between cadmium and coronary artery atherosclerosis have not been examined.Our study sought to examine the hypothesis that blood cadmium (B-Cd) is positively associated with coronary artery calcification, as a measure of coronary artery atherosclerosis in the population-based Swedish SCAPIS study.Our analysis included 5,627 individuals (51% women), age 50-64 y, enrolled from 2013 to 2018. The coronary artery calcium score (CACS) was obtained from computed tomography. Blood cadmium was determined by inductively coupled plasma mass spectrometry (ICP-MS). Associations between B-Cd and coronary artery calcium score (CACS Agatston score) were evaluated using prevalence ratios (PRs) in models adjusted for sex, age, smoking, hypertension, diabetes, low-density cholesterol/high-density cholesterol ratio, and family history.The median B-Cd concentration was 0.24μg/L. The prevalence of positive coronary artery calcium (CACS>0) was 41% and the prevalence of CACS≥100 was 13%. Relative to the lowest quartile (Q) of B-Cd (<0.16μg/L), the highest quartile (median 0.63μg/L) was associated with a small but significant increase in CACS>0 (PR 1.1; 95% CI: 1.0, 1.3), and a greater relative increase in CACS≥100 (PR 1.6; 95% CI: 1.3, 2.0). When restricted to 2,446 never-smokers, corresponding PRs were 1.1 (95% CI 0.9, 1.3) for CACS>0 (63 cases in Q4) and 1.7 (95% CI 1.1, 2.7) for CACS≥100 (17 cases in Q4).Blood cadmium in the highest quartile was associated with CACS in a general population sample with low to moderate cadmium exposure. This supports the hypothesis that atherosclerosis is an important mechanism underlying the associations between cadmium and incident cardiovascular disease. The findings suggest that public health measures to reduce cadmium exposure are warranted. https://doi.org/10.1289/EHP8523.
Circulating Soluble Fms-like Tyrosine Kinase in Renal Diseases Other than Preeclampsia
Authors: Theresa M. Wewers, Annika Schulz, Ingo Nolte, Hermann Pavenstädt, Marcus Brand, Giovana S. Di Marco
Journal: Journal of the American Society of Nephrology (2021)

Soluble Fms-like tyrosine kinase (sFlt-1/sVEGFR1) is a naturally occurring antagonist of vascular endothelial growth factor (VEGF). Despite being a secreted, soluble protein lacking cytoplasmic and transmembrane domains, sFlt-1 can act locally and be protective against excessive microenvironmental VEGF concentration or exert autocrine functions independently of VEGF. Circulating sFlt-1 may indiscriminately affect endothelial function and the microvasculature of distant target organs. The clinical significance of excess sFlt-1 in kidney disease was first shown in preeclampsia, a major renal complication of pregnancy. However, circulating sFlt-1 levels appear to be increased in various diseases with varying degrees of renal impairment. Relevant clinical associations between circulating sFlt-1 and severe outcomes (e.g., endothelial dysfunction, renal impairment, cardiovascular disease, and all-cause mortality) have been observed in patients with CKD and after kidney transplantation. However, sFlt-1 appears to be protective against renal dysfunction-associated aggravation of atherosclerosis and diabetic nephropathy. Therefore, in this study, we provide an update on sFlt-1 in several kidney diseases other than preeclampsia, discuss clinical findings and experimental studies, and briefly consider its use in clinical practice.
Return to sport decisions after an acute lateral ankle sprain injury: introducing the PAASS framework—an international multidisciplinary consensus
Authors: Michelle D Smith, Bill Vicenzino, Roald Bahr, Thomas Bandholm, Rosalyn Cooke, Luciana De Michelis Mendonça, François Fourchet, Philip Glasgow, Phillip A Gribble, Lee Herrington, Claire E Hiller, Sae Yong Lee, Andrea Macaluso, Romain Meeusen, Oluwatoyosi B A Owoeye, Duncan Reid, Bruno Tassignon, Masafumi Terada, Kristian Thorborg, Evert Verhagen, Jo Verschueren, Dan Wang, Rod Whiteley, Erik A Wikstrom, Eamonn Delahunt
Journal: British Journal of Sports Medicine (2021)

Despite being the most commonly incurred sports injury with a high recurrence rate, there are no guidelines to inform return to sport (RTS) decisions following acute lateral ankle sprain injuries. We aimed to develop a list of assessment items to address this gap.We used a three-round Delphi survey approach to develop consensus of opinion among 155 globally diverse health professionals working in elite field or court sports. This involved surveys that were structured in question format with both closed-response and open-response options. We asked panellists to indicate their agreement about whether or not assessment items should support the RTS decision after an acute lateral ankle sprain injury. The second and third round surveys included quantitative and qualitative feedback from the previous round. We defined a priori consensus being reached at >70% agree or disagree responses.Sixteen assessment items reached consensus to be included in the RTS decision after an acute lateral ankle sprain injury. They were mapped to five domains with 98% panellist agreement-PAASS: Pain (during sport participation and over the last 24 hours), Ankle impairments (range of motion; muscle strength, endurance and power), Athlete perception (perceived ankle confidence/reassurance and stability; psychological readiness), Sensorimotor control (proprioception; dynamic postural control/balance), Sport/functional performance (hopping, jumping and agility; sport-specific drills; ability to complete a full training session).Expert opinion indicated that pain severity, ankle impairments, sensorimotor control, athlete perception/readiness and sport/functional performance should be assessed to inform the RTS decision following an acute lateral ankle sprain injury.ACTRN12619000522112.
Abstract 450: Rapid Cycle Deliberate Practice Improves Critical Item Retrieval From Crash Cart
Authors: Julia Cotteral, Keri Kekkonen, Richard L Fidler
Journal: Circulation (2019)

Introduction: Unfamiliarity with crash cart contents contributes to decreased patient safety. There is no standardization of crash carts organization or contents. Initial moments of an emergency are critical and especially stressful. Responders familiar with the available equipment may be more efficient in retrieval and utilization of supplies. Methods: This study investigated the effects of Rapid Cycle Deliberate Practice (RCDP) as a training tool to increase familiarity with crash carts and contents, through a challenge of timed retrieval and assembly of critical items needed in response to in-hospital cardiac arrest (IHCA). Individuals were randomly assigned to one of four experimental groups to further identify efficient education methods. Hypothesis: RCDP predicted to improve retrieval performance and participant group assigned to hands-on discovery of the crash cart would show most improvement. Results: 75 interdisciplinary participants averaged total time for retrieval of 12 critical care items with completion of 4 corresponding tasks of 327 seconds decreased to 104 seconds from round 1 to 2. Secondly, average number of drawer pulls to retrieve items went from 14.8 to 10.5. The item most infrequently found in the 60 seconds allotted in round 1 was the intraosseous access kit (14/75, 18.67%). Connection of the defibrillator electrodes to the defibrillator device failed completion by 23 participants (30.67%) in the 60-second round 1. Retrieval of intraosseous access kit and connection of defibrillator electrodes was successful by all participants in round 2. Conclusions: Findings highlight the importance of training staff on available emergency equipment, with the expectation that increased familiarity and decreased response times will correlate to improved patient IHCA outcomes. Furthermore, findings indicate a need for standardization of crash cart organization across units and facilities.
臨床ケアと研究における神経膠腫患者報告転帰評価:神経腫瘍学共同報告における反応評価【JST・京大機械翻訳】
Authors: Armstrong Terri S, Dirven Linda, Arons David, Bates Amanda, Chang Susan M, Coens Corneel, Espinasse Claire, Gilbert Mark R, Jenkinson David, Kluetz Paul, Mendoza Tito, Rubinstein Larry, Sul Joohee, Weller Michael, Wen Patrick Y, van den Bent Martin J, Taphoorn Martin J B
Journal: The Lancet Oncology (2020)
Abstract 378: Diagnosing Pneumonia After Cardiac Arrest
Authors: Alexandra Weissman, Jacob S Puyana, David Spencer, Melissa Repine, Jon C Rittenberger, Clifton W Callaway
Journal: Circulation (2019)

Introduction: Post cardiac arrest syndrome, therapeutic hypothermia, and CPR confound the clinical diagnosis of pneumonia. Accurate pneumonia diagnosis is required to improve targeted antibiotic allocation and prevent sequelae of untargeted antibiotic therapy. Hypothesis: We can rigorously define pneumonia after cardiac arrest (CA) using accepted clinical parameters adapted from existing guidelines and innate immune system biomarkers Interleukin-17A (IL-17A), integrin α9β1, and CD11b specific to the response to pulmonary infection. Methods: A prospective cohort of consecutive OHCA patients surviving at least 72 hours from arrival was enrolled. IL-17A, integrin α9β1, and CD11b were measured daily at 4 timepoints from time 0 (arrival) through 72 hours. Chest radiography, pulmonary microbiology, temperature, and white blood cell count were recorded concurrently from the medical record. Pneumonia was defined narrowly (pna_narrow) by the presence of at least 2 of the following criteria in the initial 72 hours of presentation: fever ≥38°C; persistent infiltrate on chest radiography; positive sputum or bronchoalveolar lavage per the hospital microbiology laboratory. Broad criteria (pna_broad) also incorporated persistent leukocytosis ≥15,000 or leukopenia &lt;3,000. Results: Of the 56 subjects with all data, 23% (13 of 56) met pna_narrow criteria while 43% (24 of 56) met pna_broad criteria. Positive clinical pulmonary microbiology was present in 62% (8 of 13) subjects meeting pna_narrow and 46% (11 of 24) subjects meeting pna_broad criteria. Antibiotics were given to 65% (28 of 43) subjects without pna_narrow and 63% (20 of 32) without pna_broad. Overall, 70% (39 of 56) subjects received antibiotics regardless of pneumonia status. Integrin α9β1 at Time 28 hours and Time 72 hours was associated with pna_narrow (p = 0.010, p = 0.049). CD11b at Time 0 and 72 hours was associated with pna_narrow (p = 0.03, p = 0.049). IL-17 at Time 28 and Time 72 was associated with pna_narrow (p = 0.04, p = 0.01). Conclusions: Pneumonia was rigorously defined in 23 to 43% of our sample, yet 70% of subjects received antibiotics. More rigorous definitions for pneumonia after CA, combined with pulmonary infection biomarkers, could be used to improve diagnosis and antibiotic allocation.