tbuckley/cabot-search huggingface dataset:
Abstract 9018: Serial in vivo Imaging Reveals a Key Function for Splenic Monocytes in Infarct Healing
Authors: Florian Leuschner, Philipp J Rauch, Rostic Gorbatov, Brett Marinelli, Won Woo Lee, Brena Sena, Peter Panizzi, Peter Libby, Mikael J Pittet, Filip K Swirski, Ralph Weissleder, Matthias Nahrendorf
Journal: Circulation (2011)

The splenic monocyte reservoir contributes substantially to acute inflammation, and these cells participate centrally in tissue repair after myocardial infarction (MI). We here investigated the relevance of the splenic reservoir monocytes for infarct healing and left ventricular remodeling. Methods: Mice received coronary artery ligation and splenectomy either on the day of MI or 3 days later, and were then followed by cardiac MRI (day 1 and 21 after MI, figure). On day 5 after MI, they underwent three-channel fluorescent molecular tomography (FMT-CT) to quantify uptake of a monocyte/macrophage-targeted fluorescent nanoparticle and a fluorescently labeled integrin probe, and activation of a protease sensor in the heart. Mice with coronary ligation but without splenectomy served as controls. Results: Removal of the spleen reduced accumulation of nanoparticles, indicating reduced monocyte/macrophage phagocytic activity in the infarct. Proteolytic potential and integrin expression were reduced as well, independent of splenectomy time (p&lt;0.05 versus MI only, figure). Splenectomy at either time-point significantly impaired left ventricular ejection fraction on MRI (MI only, 50±6%; MI and immediate splenectomy, 32±4%; MI and splenectomy 3 days later, 36±4%; p&lt;0.05 versus MI only) and resulted in a thinner scar (530±50μ m, 320±20μ m, 370±20μ m, p&lt;0.05 versus MI only). Ex vivo analysis in additional cohorts corroborated in vivo imaging data. Conclusion: Removal of the spleen reduced monocyte-mediated healing biomarkers and resulted in infarct expansion and accelerated left ventricular remodeling. Thus, spleen-derived macrophages likely promote healing of the infarcting myocardium.
Extracellular ATP and Purinergic P2Y2 Receptor Signaling Promote Liver Tumorigenesis in Mice by Exacerbating DNA Damage
Authors: Isabel Schulien, Birgit Hockenjos, Veerle van Marck, C. Korcan Ayata, Marie Follo, Robert Thimme, Peter Hasselblatt
Journal: Cancer Research (2019)

Abstract Release of ATP to the extracellular compartment and subsequent activation of purinergic receptors is a conserved mechanism mediating inflammatory responses and cell fate decisions in various organs including the liver. Previous findings suggest that extracellular ATP may promote liver tumorigenesis, however, the underlying mechanisms are poorly understood. Therefore, our aim was to dissect the functions of extracellular ATP and P2Y2 receptors (P2Y2R) during hepatocarcinogenesis. Liver tumors were induced in wild-type and P2y2r−/− knockout mice by intraperitoneal diethylnitrosamine (DEN) injection. Tumorigenesis was analyzed after 8 to 10 months and molecular analyses were performed at different stages of tumorigenesis in vivo, as well as in primary mouse hepatocytes in vitro. Liver tumor incidence and tumor numbers were strongly reduced in P2y2r−/− mice, whereas tumor size and morphology were comparable to wild-type controls, suggesting that P2Y2R contributes to tumor initiation. Mechanistically, hepatocyte proliferation in DEN-treated P2y2r−/− mice was reduced, which correlated with reduced c-JUN and CCND1 but increased p21 expression. Moreover, DNA damage as determined by hepatocellular expression of γH2A.X and of genes related to genotoxic stress, as well as STAT3 phosphorylation, was reduced in the absence of P2y2r. Administration of genotoxic agents to primary hepatocytes in vitro confirmed that DNA damage was indeed exacerbated by extracellular ATP, subsequent P2Y2R activation, and downstream intracellular calcium-dependent signal transduction. In conclusion, our data reveal that extracellular ATP and subsequent P2Y2R function stimulate DNA damage responses and hepatocyte proliferation, thereby promoting hepatocarcinogenesis. Targeting this pathway may be an attractive approach for chemoprevention of hepatocellular carcinoma. Significance: Extracellular ATP and subsequent P2Y2 receptor function stimulate DNA damage responses and hepatocyte proliferation, thereby promoting hepatocarcinogenesis in mice. Targeting this pathway may be an attractive approach for chemoprevention of hepatocellular carcinoma.
Interleukin‐5 drives glycolysis and reactive oxygen species‐dependent citric acid cycling by eosinophils
Authors: Nicholas Jones, Emma E. Vincent, Lindsey C. Felix, James G. Cronin, Louis M. Scott, Paul S. Hole, Paige Lacy, Catherine A. Thornton
Journal: Allergy (2019)

Eosinophils have been long implicated in antiparasite immunity and allergic diseases and, more recently, in regulating adipose tissue homeostasis. The metabolic processes that govern eosinophils, particularly upon activation, are unknown.
Abstract 15103: A Glycolytic Switch is Required for Transdifferentiation to Endothelial Lineage
Authors: Li Lai, Erin Reineke, Dale Hamilton, John P Cooke
Journal: Circulation (2018)

Background: Previously we have shown that activation of cell-autonomous innate immune signaling facilitates the trandifferentiation of fibroblasts into induced endothelial cells (iECs), and is requ...
Changes in m6A RNA methylation contribute to heart failure progression by modulating translation
Authors: Tea Berulava, Eric Buchholz, Vakhtang Elerdashvili, Tonatiuh Pena, Md Rezaul Islam, Dawid Lbik, Belal A. Mohamed, Andre Renner, Dirk von Lewinski, Michael Sacherer, Katherine E. Bohnsack, Markus T. Bohnsack, Gaurav Jain, Vincenzo Capece, Nicole Cleve, Susanne Burkhardt, Gerd Hasenfuss, Andre Fischer, Karl Toischer
Journal: European Journal of Heart Failure (2019)

ABSTRACT Aims Deregulation of epigenetic processes and aberrant gene expression are important mechanisms in heart failure. Here we studied the potential relevance of m6A RNA methylation in heart failure development. Methods and results We analysed m6A RNA methylation via next‐generation sequencing. We found that approximately one quarter of the transcripts in the healthy mouse and human heart exhibit m6A RNA methylation. During progression to heart failure we observed that changes in m6A RNA methylation exceed changes in gene expression both in mouse and human. RNAs with altered m6A RNA methylation were mainly linked to metabolic and regulatory pathways, while changes in RNA expression level mainly represented changes in structural plasticity. Mechanistically, we could link m6A RNA methylation to altered RNA translation and protein production. Interestingly, differentially methylated but not differentially expressed RNAs showed differential polysomal occupancy, indicating transcription‐independent modulation of translation. Furthermore, mice with a cardiomyocyte restricted knockout of the RNA demethylase Fto exhibited an impaired cardiac function compared to control mice. Conclusions We could show that m6A landscape is altered in heart hypertrophy and heart failure. m6A RNA methylation changes lead to changes in protein abundance, unconnected to mRNA levels. This uncovers a new transcription‐independent mechanisms of translation regulation. Therefore, our data suggest that modulation of epitranscriptomic processes such as m6A methylation might be an interesting target for therapeutic interventions.
Abstract 15464: Clinical Features and Impact on Clinical Outcome of Cerebral Microbleeds in Patients With Active Infective Endocarditis
Authors: Ryosuke Murai, Shuichiro Kaji, Yasuhiro Sasaki, Mitsuhiko Ota, Kitae Kim, Takeshi Kitai, Takafumi Yamane, Atsushi Kobori, Natsuhiko Ehara, Makoto Kinoshita, Yutaka Furukawa
Journal: Circulation (2015)

Background: Cerebrovascular complications are frequently observed in patients with infective endocarditis (IE). Cerebral microbleeds (CMB) are an increasingly recognized neuroimaging finding by newer MRI methodologies in patients with active IE. However, the clinical features of CMB and their impact on clinical outcomes still remain unclear. The purpose of this study was to assess the clinical features of CMB and their association with clinical outcomes. Methods: From January 2009 to June 2014, 117 patients with active IE diagnosed by modified Duke’s criteria were retrospectively reviewed. Among them, brain MRI was performed in 90 patients, and 68 patients whose MRI data were available for the assessment of CMB were finally enrolled in the current analysis. CMB were defined as T2* or susceptibility weighted imaging (SWI) hypointense lesions with a diameter &lt;10mm. Results: Of the 68 patients, 34 showed CMB (CMB group) and 34 did not (non-CMB group). The incidences of concomitant cerebral infarction (CMB vs non-CMB: 56% vs 47%, p=0.63) and cerebral hemorrhage (16% vs 21%, p=0.72) were comparable between the groups. There were also no significant difference in the incidence of symptomatic cerebral complications (24% vs 35%, p=0.43). It is noteworthy that significantly high prevalence of Staphylococcal IE was observed in CMB group (38% vs 12%, p=0.014). Diseased valves were not differ between the groups, but more patients with prosthetic valve endocarditis (PVE) were included in CMB group (35% vs 3%, p&lt;0.01). Surgical intervention was performed in 24 (71%) patients in CMB group and 23 (68%) in non-CMB. There were no significant difference in the incidences of de novo stroke following cardiac surgery (17% vs 13%, p=1.00). In-hospital mortality rate and estimated 1-year major adverse event-free rate between two groups were not significantly different (8.8% vs 8.8%, p=1.00; 85% vs 88%, p=0.40, respectively). Conclusions: CMB in IE patients were associated with high prevalence of Staphylococcal IE and PVE. However, CMB were not a predictor of poorer in-hospital and mid-term clinical outcomes.
Abstract B29: Outcomes of DNA repair-deficient pancreatic cancers: KU Cancer Center experience
Authors: Anup Kasi, Suhaib Bajwa, Mohammed Al-Jumayli, Anwaar Saeed, Andrew Godwin
Journal: Cancer Research (2019)

Abstract Background: DNA repair-defective pancreatic cancers are a subset that could be exploited therapeutically. BRCA 1 and 2 deficient pancreatic cancers have shown improved survival outcomes with platinum-based chemotherapy and/or PARP inhibitors. However, survival outcomes of pancreatic cancers harboring other DNA repair defects are not well understood. Methods: We retrospectively evaluated survival outcomes of 60 metastatic pancreatic cancer patients who had their tumors profiled by standard-of-care next-generation sequencing. Patients with deficient DNA repair genes such as BRCA1 (n=2), BRCA2 (n=12), ATM (n=7), PALB2 (n=1), NBN (n=1), and BRIP1 (n=1) were grouped into DNA repair-deficient group. The remaining patients were grouped into DNA repair-proficient group. Comparative survival analysis between the two groups was performed using Kaplan-Meir methods. Results: Demographic/baseline data for the DNA repair-deficient group (n=22) vs. the proficient group (n=38) are compared as follows: 12 vs. 20 males, 10 vs. 18 females, 20 vs. 33 with ECOG scores 0-1, 1 vs. 4 with a ECOG score 2+, 12 vs. 19 with tumors in the head, 7 vs. 6 with tumors in the body, 4 vs. 12 with tumors in the tail, 4 vs. 10 with a CA 19-9 of &amp;lt;34, 12 vs. 24 with a CA 19-9 of &amp;gt;34, 7 vs. 19 received initial gemcitabine-based therapy, and 15 vs. 19 received initial FOLFIRINOX chemotherapy. Survival analysis in DNA repair-deficient vs. proficient group revealed comparable median PFS of 7 months (95%CI 5-32 months) vs. 7 months (95% CI 4-30 months) [HR 0.97, p=0.9] but a longer median OS of 18 months vs. 12 months [HR 0.51, p=0.07]. Among DNA repair-deficient group, median OS was 12 months for patients who received first-line platinum-based chemo (n=15) vs. 5 months for first-line non-platinum chemo (n=7) [HR 0.57, p=0.39]. Conclusion: In addition to BRCA1/2 deficiency, pancreatic cancers that harbor other DNA repair defects also show trend towards improved OS when compared to DNA repair-proficient cancers. Treatment with first-line platinum-based chemo favored better OS in DNA repair-deficient cancers. Though median PFS appears comparable, the upper limit of 95% CI for PFS is higher for the DNA repair-deficient cancers. These findings did not meet statistical significance given our small sample size and need to be validated in a larger cohort. We currently have an ongoing clinical trial to investigate DNA repair defects in addition to BRCA1/2 in pancreatic cancers (NCT03553004). Citation Format: Anup Kasi, Suhaib Bajwa, Mohammed Al-Jumayli, Anwaar Saeed, Andrew Godwin. Outcomes of DNA repair-deficient pancreatic cancers: KU Cancer Center experience [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B29.
Hypertension in Relation to Dioxins and Polychlorinated Biphenyls from the Anniston Community Health Survey Follow-Up
Authors: Marian Pavuk, Tara C. Serio, Caroline Cusack, Matt Cave, Paula F. Rosenbaum, Linda S. Birnbaum
Journal: Environmental Health Perspectives (2019)

Background: In 2014, we conducted a longitudinal study [Anniston Community Health Survey (ACHS II)] 8 y after the baseline (ACHS I). Objectives: We investigated the relationship between persistent chlorinated compounds and hypertension in residents living around the former polychlorinated biphenyl (PCB) production plant in Anniston, Alabama. We also examined the potential role of inflammatory cytokines in those with hypertension. Methods: A total of 338 participants had their blood pressure measured and medications recorded, gave a blood sample, and completed a questionnaire. Prevalent hypertension was defined as taking antihypertensive medication or having systolic blood pressure >140 mmHg and/or diastolic pressure >90 mmHg; incident hypertension used similar criteria in those who developed hypertension since the baseline in 2005–2007. PCB congeners were categorized into structure–activity groups, and toxic equivalencies (TEQs) were calculated for dioxin-like compounds. Descriptive statistics, logistic and linear regressions, as well as Cox proportional hazard models, were used to analyze the associations between exposures and hypertension. Results: Prevalent hypertension (78%) in ACHS II showed statistically significant adjusted odds ratios (ORs) for PCBs 74, 99, 138, 153, 167, 177, 183, and 187, ranging from 2.18 [95% confidence interval (CI): 1.10, 4.33] to 2.76 (95% CI: 1.14, 6.73), as well as for two estrogenic-like PCB groups, and the thyroid-like group [ORs ranging from 2.25 (95% CI: 1.07, 4.75) to 2.54 (95% CI: 1.13, 5.74)]. Furthermore, analysis of quartiles demonstrated a monotonic relationship for dioxin-like non-ortho (non-o)-PCB TEQs [fourth vs. first quartile: 3.66 (95% CI: 1.40, 9.56)]. Longitudinal analyses of incident hypertension supported those positive associations. The results were strongest for the di-o-PCBs [hazard ratio (HR)=1.93 (95% CI: 0.93, 4.00)] and estrogenic II PCB group [HR=1.90 (95% CI: 0.96, 3.78)] but were weaker for the dioxin TEQs. Discussion: Findings supportive of positive associations were reported for dioxin-like mono-o- and non-o-PCBs as well as for nondioxin-like estrogenic and thyroid-like congeners with prevalent and incident hypertension, suggesting that multiple pathways may be involved in hypertension development. https://doi.org/10.1289/EHP5272
Impact of Prior Lines of Systemic Therapy (PST) on the Efficacy Of Cemiplimab, a Human Monoclonal Anti–PD-1, in Patients (PTS) with Advanced Cutaneous Squamous Cell Carcinoma (CSCC)
Authors: D. Rischin, N.I. Khushalani, C.D. Schmults, A. Guminski, A.L.S. Chang, K.D. Lewis, A.M. Lim, L. Hernandez-Aya, B.G.M. Hughes, D. Schadendorf, A. Hauschild, E. Stankevich, J. Booth, S. Li, Z. Chen, J. Desai, I. Lowy, M.G. Fury, M.R. Migden
Journal: Annals of Oncology (2019)
Type 2 refractory celiac disease on third-generation capsule endoscopy and enteroscopy: typical appearance of ulcerative jejunitis
Authors: Jean-Philippe Le Mouel, Mathurin Fumery, Sami Hakim, Clara Yzet, Alexandra Dervaux, Xavier Dray, Eric Nguyen-Khac
Journal: Endoscopy (2019)

We report the case of a 43-year-old woman with a medical history of active smoking who presented with abdominal pain that had appeared 4 months ago. The physical examination revealed periumbilical pain associated with weight loss. Laboratory studies revealed elevated inflammatory markers (C-reactive protein: 54 mg/dL) and hypoalbuminemia (22 g/L). Abdominal computed tomography (CT) and magnetic resonance enterography (MRE) showed a thickening of the small bowel at the junction between the jejunum and ileum, at 30 cm, suggesting Crohn’s disease. Gastroscopy showed an appearance of duodenal villous atrophy, confirmed by Marsh stage 3c biopsy findings. Anti-transglutaminase antibodies were positive at 17 U/ml. 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) detected a jejunoileal accumulation of 18F-FDG, with a standard uptake value (SUV) at of 8.1. Small-bowel capsule endoscopy confirmed the appearance of villous atrophy with the presence of sporadic ulceration ([Fig. 1]), then a completely ulcerated jejunoileal segment over several tens of centimeters, with necrotic pseudomembranous and hemorrhagic spots ([Fig. 2], [Video 1]). Biopsies of this ulcerated area were performed with double-balloon enteroscopy ([Fig. 3]), histological examination revealing refractory type 2 celiac disease (RCD) characterized by an increased clonal population of abnormal intraepithelial lymphocytes (IEL). Abnormal IEL phenotype was described with disappearance of the classical markers such as CD4 or CD5 and the presence of NKp46 marker, but without any sign of high-grade lymphoma ([Fig. 4]). Systemic corticosteroid therapy was initiated but did not improve the patient’s symptoms. She developed an occlusive syndrome requiring surgical resection of the ulcerated jejunoileal segment (39 cm). The surgical follow-up was simple. The diagnosis of type 2 RCD without high-grade lymphoma was confirmed. Gluten-free diet and open-capsule budesonide treatment were initiated with close surveillance of the patient due to the high risk of progression to T-cell lymphoma.
The need for speed: observational study of physician driving behaviors
Authors: André Zimerman, Christopher Worsham, Jaemin Woo, Anupam B Jena
Journal: BMJ (2019)

Abstract Objective To determine whether fast driving, luxury car ownership, and leniency by police officers differ across medical specialties. Design Observational study. Setting Florida, USA. Participants 5372 physicians and a sample of 19 639 non-physicians issued a ticket for speeding during 2004-17. Main outcome measures Observed rates of extreme speeding (defined as driving &gt;20 mph above the speed limit), luxury car ownership, and leniency of the speeding ticket by police officers, by physician specialty, after adjustment for age and sex. Results The sample included 5372 physicians who received 14 560 speeding tickets. The proportion of drivers who were reported driving at speeds greater than 20 mph was similar between physicians and a sample of 19 639 non-physicians who received a ticket for speeding (26.4% v 26.8% of tickets, respectively). Among physicians who received a ticket, psychiatrists were most likely to be fined for extreme speeding (adjusted odds ratio of psychiatry compared with baseline specialty of anesthesia 1.51, 95% confidence interval 1.07 to 2.14). Among drivers who received a ticket, luxury car ownership was most common among cardiologists (adjusted proportion of ticketed cardiologists who owned a luxury car 40.9%, 95% confidence interval 35.9% to 45.9%) and least common among physicians in emergency medicine, family practice, pediatrics, general surgery, and psychiatry (eg, adjusted proportion of luxury car ownership among family practice physicians 20.6%, 95% confidence interval 18.2% to 23.0%). Speed discounting, a marker of leniency by police officers in which ticketed speed is recorded at just below the threshold at which a larger fine would otherwise be imposed, was common, but rates did not differ by specialty and did not differ between physicians and a sample of non-physicians. Conclusions Rates of extreme speeding were highest among psychiatrists who received a ticket, whereas cardiologists were the most likely to be driving a luxury car when ticketed. Leniency by police officers was similar across specialties and between physicians and non-physicians.
FSTL-1 Attenuation Causes Spontaneous Smoke-Resistant Pulmonary Emphysema
Authors: Matthew Henkel, Jessica Partyka, Alyssa D. Gregory, Erick Forno, Michael H. Cho, Taylor Eddens, Andrew R. Tout, Nathan Salamacha, William Horne, Krithika S. Rao, Yijen Wu, John F. Alcorn, Dennis Kostka, Raphael Hirsch, Juan C. Celedón, Steven D. Shapiro, Jay K. Kolls, Brian T. Campfield
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Rationale: The role of FSTL-1 (follistatin-like 1) in lung homeostasis is unknown.Objectives: We aimed to define the impact of FSTL-1 attenuation on lung structure and function and to identify FSTL-1-regulated transcriptional pathways in the lung. Further, we aimed to analyze the association of FSTL-1 SNPs with lung disease.Methods: FSTL-1 hypomorphic (FSTL-1 Hypo) mice underwent lung morphometry, pulmonary function testing, and micro-computed tomography. Fstl1 expression was determined in wild-type lung cell populations from three independent research groups. RNA sequencing of wild-type and FSTL-1 Hypo mice identified FSTL-1-regulated gene expression, followed by validation and mechanistic in vitro examination. FSTL1 SNP analysis was performed in the COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) cohort.Measurements and Main Results: FSTL-1 Hypo mice developed spontaneous emphysema, independent of smoke exposure. Fstl1 is highly expressed in the lung by mesenchymal and endothelial cells but not immune cells. RNA sequencing of whole lung identified 33 FSTL-1-regulated genes, including Nr4a1, an orphan nuclear hormone receptor that negatively regulates NF-κB (nuclear factor-κB) signaling. In vitro, recombinant FSTL-1 treatment of macrophages attenuated NF-κB p65 phosphorylation in an Nr4a1-dependent manner. Within the COPDGene cohort, several SNPs in the FSTL1 region corresponded to chronic obstructive pulmonary disease and lung function.Conclusions: This work identifies a novel role for FSTL-1 protecting against emphysema development independent of smoke exposure. This FSTL-1-deficient emphysema implicates regulation of immune tolerance in lung macrophages through Nr4a1. Further study of the mechanisms involving FSTL-1 in lung homeostasis, immune regulation, and NF-κB signaling may provide additional insight into the pathophysiology of emphysema and inflammatory lung diseases.