tbuckley/cabot-search huggingface dataset:
Abstract 18255: Inhibition of Toll-Like Receptor 4 Attenuates Angiotensin II-Induced Abdominal Aortic Aneurysm Formation: Role of STAT3
Authors: Yali Zhang, Ho-Jin Park, Debbie Beasley, Jonas Galper
Journal: Circulation (2013)

Abdominal aortic aneurysm (AAA) is a potentially life-threatening degenerative vascular disease that affects 6-9% of men over 65. Toll-like receptors (TLRs) mediate the innate immune response resulting in the recruitment of inflammatory cells to the site of a range of pathogen-associated molecular patterns; they have also been implicated in many other inflammatory diseases such as cancer and atherosclerosis. It has been suggested by others that TLR4 might play a role in AAA formation. Objective: The purpose of this study was to determine whether TLR4 and its related Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling pathway contributed to the development of angiotensin II (AngII)-induced AAA formation. Methods and Results: AngII (750 ng/kg/min) was infused into either ApoE-/- or ApoE-/-TLR4-/- male mice at 4 month old for 28 days using osmotic minipumps. The expression of TLR4 protein was significantly increased in aneurismal tissues compared to control aorta. TLR4 deficiency profoundly reduced AAA, with incidence of AAA formation of 82% versus 39%, with external aortic diameters of 1.88±0.13 mm versus 1.28±0.20 mm (n=18) respectively. STAT3 activation as measured by levels of pSTAT3 was increased in AngII treated ApoE-/- mice compared to vehicle treated, and was markedly reduced in AngII treated ApoE-/-TLR4-/- mice. Furthermore, the TLR4 antagonist, Eritoran attenuated AAA formation, with incidence of AAA formation of 80% versus 50%, with external aortic diameters of 1.92±0.15 mm versus 1.35±0.18 mm (n=9) respectively. Eritoran treatment also decreased pSTAT3 in AngII-treated ApoE-/- mice. The JAK/STAT3 can be driven by both AngII and TLR4 signaling. In order to determine the role of STAT3 in AAA formation, S3I-201, an inhibitor of STAT3 was administrated. AngII-induced AAA formation in ApoE-/- was significantly prevented by S3I-201 treatment (5mg/kg, IP, QOD) with incidence of AAA formation of 85% versus 40%, with external aortic diameters of 1.90±0.16 mm versus 1.15±0.10 mm (n=15) respectively. Conclusions: These studies demonstrated that inhibition of TLR4 reduces AngII-induced AAA via a STAT3 dependent mechanism suggesting that selective targeting of STAT3 may have substantial therapeutic potential.
MUSCLEMOTION
Authors: Luca Sala, Berend J. van Meer, Leon G.J. Tertoolen, Jeroen Bakkers, Milena Bellin, Richard P. Davis, Chris Denning, Michel A.E. Dieben, Thomas Eschenhagen, Elisa Giacomelli, Catarina Grandela, Arne Hansen, Eduard R. Holman, Monique R.M. Jongbloed, Sarah M. Kamel, Charlotte D. Koopman, Quentin Lachaud, Ingra Mannhardt, Mervyn P.H. Mol, Diogo Mosqueira, Valeria V. Orlova, Robert Passier, Marcelo C. Ribeiro, Umber Saleem, Godfrey L. Smith, Francis L. Burton, Christine L. Mummery
Journal: Circulation Research (2017)

Rationale: There are several methods to measure cardiomyocyte and muscle contraction, but these require customized hardware, expensive apparatus, and advanced informatics or can only be used in single experimental models. Consequently, data and techniques have been difficult to reproduce across models and laboratories, analysis is time consuming, and only specialist researchers can quantify data. Objective: Here, we describe and validate an automated, open-source software tool (MUSCLEMOTION) adaptable for use with standard laboratory and clinical imaging equipment that enables quantitative analysis of normal cardiac contraction, disease phenotypes, and pharmacological responses. Methods and Results: MUSCLEMOTION allowed rapid and easy measurement of movement from high-speed movies in (1) 1-dimensional in vitro models, such as isolated adult and human pluripotent stem cell-derived cardiomyocytes; (2) 2-dimensional in vitro models, such as beating cardiomyocyte monolayers or small clusters of human pluripotent stem cell-derived cardiomyocytes; (3) 3-dimensional multicellular in vitro or in vivo contractile tissues, such as cardiac “organoids,” engineered heart tissues, and zebrafish and human hearts. MUSCLEMOTION was effective under different recording conditions (bright-field microscopy with simultaneous patch-clamp recording, phase contrast microscopy, and traction force microscopy). Outcomes were virtually identical to the current gold standards for contraction measurement, such as optical flow, post deflection, edge-detection systems, or manual analyses. Finally, we used the algorithm to quantify contraction in in vitro and in vivo arrhythmia models and to measure pharmacological responses. Conclusions: Using a single open-source method for processing video recordings, we obtained reliable pharmacological data and measures of cardiac disease phenotype in experimental cell, animal, and human models.
Катеринославські лікарі німецького походження
Authors: M.P. Chaban, Z.I. Shevtsova, V.V. Gaponov
Journal: GASTROENTEROLOGY (2017)

Вивчено життєвий шлях і професійну діяльність медиків німецького походження на Катеринославщині в ХVІІІ–ХІХ століттях. Серед них Карл Роде, Іван Зегер, Іван Зоммер, Олександр Грунау, Яків Езау, Роберт Вебер. Розглянуто їх внесок у розвиток науки, надання медичної допомоги населенню.
Genetic Architecture of the Cardiovascular Risk Proteome
Authors: Mark D. Benson, Qiong Yang, Debby Ngo, Yineng Zhu, Dongxiao Shen, Laurie A. Farrell, Sumita Sinha, Michelle J. Keyes, Ramachandran S. Vasan, Martin G. Larson, J. Gustav Smith, Thomas J. Wang, Robert E. Gerszten
Journal: Circulation (2017)

We recently identified 156 proteins in human plasma that were each associated with the net Framingham Cardiovascular Disease Risk Score using an aptamer-based proteomic platform in Framingham Heart Study Offspring participants. Here we hypothesized that performing genome-wide association studies and exome array analyses on the levels of each of these 156 proteins might identify genetic determinants of risk-associated circulating factors and provide insights into early cardiovascular pathophysiology.We studied the association of genetic variants with the plasma levels of each of the 156 Framingham Cardiovascular Disease Risk Score-associated proteins using linear mixed-effects models in 2 population-based cohorts. We performed discovery analyses on plasma samples from 759 participants of the Framingham Heart Study Offspring cohort, an observational study of the offspring of the original Framingham Heart Study and their spouses, and validated these findings in plasma samples from 1421 participants of the MDCS (Malmö Diet and Cancer Study). To evaluate the utility of this strategy in identifying new biological pathways relevant to cardiovascular disease pathophysiology, we performed studies in a cell-model system to experimentally validate the functional significance of an especially novel genetic association with circulating apolipoprotein E levels.We identified 120 locus-protein associations in genome-wide analyses and 41 associations in exome array analyses, the majority of which have not been described previously. These loci explained up to 66% of interindividual plasma protein-level variation and, on average, accounted for 3 times the amount of variation explained by common clinical factors, such as age, sex, and diabetes mellitus status. We described overlap among many of these loci and cardiovascular disease genetic risk variants. Finally, we experimentally validated a novel association between circulating apolipoprotein E levels and the transcription factor phosphatase 1G. Knockdown of phosphatase 1G in a human liver cell model resulted in decreased apolipoprotein E transcription and apolipoprotein E protein levels in cultured supernatants.We identified dozens of novel genetic determinants of proteins associated with the Framingham Cardiovascular Disease Risk Score and experimentally validated a new role for phosphatase 1G in lipoprotein biology. Further, genome-wide and exome array data for each protein have been made publicly available as a resource for cardiovascular disease research.
Single-cell profiling of human gliomas reveals macrophage ontogeny as a basis for regional differences in macrophage activation in the tumor microenvironment
Authors: Sören Müller, Gary Kohanbash, S. John Liu, Beatriz Alvarado, Diego Carrera, Aparna Bhaduri, Payal B. Watchmaker, Garima Yagnik, Elizabeth Di Lullo, Martina Malatesta, Nduka M. Amankulor, Arnold R. Kriegstein, Daniel A. Lim, Manish Aghi, Hideho Okada, Aaron Diaz
Journal: Genome biology (2017)

Tumor-associated macrophages (TAMs) are abundant in gliomas and immunosuppressive TAMs are a barrier to emerging immunotherapies. It is unknown to what extent macrophages derived from peripheral blood adopt the phenotype of brain-resident microglia in pre-treatment gliomas. The relative proportions of blood-derived macrophages and microglia have been poorly quantified in clinical samples due to a paucity of markers that distinguish these cell types in malignant tissue. We perform single-cell RNA-sequencing of human gliomas and identify phenotypic differences in TAMs of distinct lineages. We isolate TAMs from patient biopsies and compare them with macrophages from non-malignant human tissue, glioma atlases, and murine glioma models. We present a novel signature that distinguishes TAMs by ontogeny in human gliomas. Blood-derived TAMs upregulate immunosuppressive cytokines and show an altered metabolism compared to microglial TAMs. They are also enriched in perivascular and necrotic regions. The gene signature of blood-derived TAMs, but not microglial TAMs, correlates with significantly inferior survival in low-grade glioma. Surprisingly, TAMs frequently co-express canonical pro-inflammatory (M1) and alternatively activated (M2) genes in individual cells. We conclude that blood-derived TAMs significantly infiltrate pre-treatment gliomas, to a degree that varies by glioma subtype and tumor compartment. Blood-derived TAMs do not universally conform to the phenotype of microglia, but preferentially express immunosuppressive cytokines and show an altered metabolism. Our results argue against status quo therapeutic strategies that target TAMs indiscriminately and in favor of strategies that specifically target immunosuppressive blood-derived TAMs.
Abstract 18204: Generalizability Of The Paradigm-HF Trial For The Use Of Sacubitril/Valsartan In A Tertiary Care Outpatient Heart Failure Patient Population
Authors: Julia Sackheim, Doris Chan, Kelly Beers, Hassan Khan, Lampros Papadimitriou, Michelle W Bloom, Javed Butler, Hal Skopicki
Journal: Circulation (2016)

Background: The combination of sacubitril/valsartan was recently approved for treatment of symptomatic heart failure and reduced ejection fraction (HFrEF). However, the run-in phase and inclusion/e...
Tumor oxygenation using with the recombinant human serum albumin incorporating synthetic heme (rHSA-FeP) and the hemoglobin-vesicle (HbV) in a rat LY80 tumor model
Authors: Arifumi Iwamaru, Masazumi Watanabe, Yotaro Izumi, Hirohisa Horinouchi, Hiromi Sakai, Teruyuki Komatsu, Eishun Tsuchida, Kouichi Kobayashi
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

4132 

Current investigations suggested that hypoxic cells within the tumor have the potential resistance against chemotherapy or radiotherapy. These observations suggest that tumor oxygenation may play the important role in cancer treatment. Recently, we have developed two different types of artificial oxygen carriers. One is an artificial hemoprotein (rHSA-FeP), recombinant human serum albumin (rHSA) incorporating synthetic hemes, the tetrakis (o-pivalamido) phenylporphinatoiron (II) derivative. The other is hemoglobin vesicle (HbV), which is the red blood cell substitute encapsulating purified concentrated Hb in a phospholipid vesicle. This research is intended as an investigation of tumor oxygenation using with these new artificial oxygen carriers. We made a rat tumor model in which ascites hepatoma LY80 was implanted to the right femoral. And we compared the efficacy of artificial oxygen carriers as shown above. The LY80 tumor cells (approximately 3000000 cells, 0.03 ml) were injected into the right thigh of a Donryu rat 1 week before experiment. At the experiment, rats were maintained by mechanical ventilation with 1% halocen and 99% oxygen. The systemic oxygen pressure level was kept at approximately 400 Torr, and there were no differences in the basal values of each measurement among the rHSA-FeP, HbV, and rHSA (control) administration groups. Each solution saturated by oxygen was injected at the rate of 2.5 ml/min/kg, via a catheter placed at the bifurcation of iliac arteries. Using with the phpsphorescence lighting system, the average partial oxygen pressure of LY80 tumor was estimated throughout and after administration every 30 seconds. The measurement was continued for 15 minutes. The oxygen pressure of the tumor before administration was obviously low (range 1.4-1.7 Torr). The administration of the rHSA-FeP solution significantly increased the oxygen pressure of the tumor up to 3.45± 1.17 Torr, which corresponds to a 2.5-fold increase compared to that of the baseline value (P = 0.014). The administration of the HbV solution also increased the oxygen pressure of the tumor up to 2.54±1.47 Torr, which corresponds to a 1.8-fold increase compared to that of the baseline value (P = 0.048). The administration of the rHSA solution did not change the oxygen pressure of the tumor. The result can be interpreted that the artificial oxygen carriers pierced the tumor vessels, where erythrocytes could not transported oxygen to the hypoxic cells within the tumor. We conclude that the rHSA-FeP and HbV were potent useful agents with regard to tumor oxygenation. Tumor oxygenation, which may have synergistic effect with other cytotoxic therapy, merits further investigation.
Exposure to Low-Dose Ionizing Radiation From Cardiac Procedures and Malignancy Risk in Adults With Congenital Heart Disease
Authors: Sarah Cohen, Aihua Liu, Michelle Gurvitz, Liming Guo, Judith Therrien, Claudie Laprise, Jay S. Kaufman, Michal Abrahamowicz, Ariane J. Marelli
Journal: Circulation (2017)

Background: Adults with congenital heart disease (CHD) are exposed to increasing amounts of low-dose ionizing radiation (LDIR) from cardiac procedures. Cancer prevalence in this population is higher than in the general population. This study estimates the association between LDIR exposure from cardiac procedures and incident cancer in adult patients with CHD. Methods: The study population derived from the Quebec Congenital Heart Disease Database. We measured cumulative numbers of LDIR-related cardiac procedures for each patient until 1 year before the time of cancer diagnosis or administrative censoring. To assess the association between LDIR exposure and cancer risk, we conducted a nested case-control study and matched cancer cases with controls on sex, CHD severity, birth year, and age. Results: The study included 24 833 adult patients with CHD aged 18 to 64 years from 1995 to 2009. In &gt;250 791 person-years of follow-up, 602 cancer cases were observed (median age, 55.4 years). The cumulative incidence of cancer estimated up to 64 years of age was 15.3% (95% confidence interval [CI], 14.2–16.5). Cases had more LDIR-related cardiac procedures than controls (1410 versus 921 per 1000 adult patients with CHD, P &lt;0.0001). Cumulative LDIR exposure was independently associated with cancer (odds ratio [OR], 1.08 per procedure; 95% CI, 1.04–1.13). Similar results were obtained by using dose estimates for LDIR exposure (OR, 1.10 per 10 mSv; 95% CI, 1.05–1.15) with a possible dose-related response. The effect measure was in the same direction, and the association was persistent for exposure from ≥6 procedures in all sensitivity analyses: after excluding most smoking-related cancer cases (OR, 1.10 per procedure; 95% CI, 1.05–1.16 and OR when exposure from ≥6 procedures, 3.08; 95% CI, 1.77–5.37), and after applying a 3-year lag period (OR, 1.09 per procedure; 95% CI, 1.03–1.14 and OR when exposure from ≥6 procedures: 2.58; 95% CI, 1.43–4.69). Conclusions: To our knowledge, this is the first large population-based study to analyze and document the association between LDIR-related cardiac procedures and incident cancer in the population of adults with CHD. Confirmations of these findings by prospective studies are needed to reinforce policy recommendations for radiation surveillance in patients with CHD where no regulation currently exists. Physicians ordering and performing cardiac imaging should ensure that exposure is as low as reasonably achievable without sacrificing quality of care.
Sorveglianza della resistenza antimicrobica in Danimarca
Authors: D. L. Monnet, H. D. Hemborg, S. R Andersen, C Schöller, T. L. Sørensen, F Bager
Journal: Eurosurveillance (2000)

Secondo gli ultimi risultati del DANMAP (Programma integrato danese di sorveglianza e ricerca sulla resistenza agli agenti antimicrobici) in Danimarca i livelli di resistenza della Salmonella enterica sono deboli. La resistenza dei ceppi di Escherichia coli patogeni per gli animali dovrebbe essere considerata come un serbatoio di resistenza piuttosto che una minaccia per la salute pubblica. Inoltre, la resistenza dei ceppi clinici di Escherichia coli segue lo stesso andamento dei profili d'uso degli antibiotici nel paese. Rimane rara la resistenza dello Staphylococcus aureus e dello Streptococcus pneumoniae. Tuttavia, e preoccupante la recente emergenza della resistenza dello S. pneumoniae alla penicillina e alla eritromicina. Infine, la sorveglianza della resistenza dei batteri commensali negli animali destinati al consumo umano e negli alimenti, mostra l'impatto positivo di misure quali l'interdizione dell'uso di antibiotici come promotori della crescita negli animali da allevamento.
Transplanted Human Microbiota and Enteric Pathogen Challenge Enhanced Susceptibility to Allergen-Mediated Asthma in a Murine Model
Authors: Susan L. Ewart, Julia A. Bell, Daniel J. Claiborne, Alexander T. Zanetti, Lindsey Lund, Syed H. Arshad, Linda S. Mansfield
Journal: Journal of Allergy and Clinical Immunology (2018)
Annals Story Slam - Just One More Question
Authors: Joel A. Fein
Journal: Annals of Internal Medicine (2017)

Web Exclusives19 December 2017Annals Story Slam - Just One More QuestionFREEJoel A. Fein, MD, MPHJoel A. Fein, MD, MPHChildren's Hospital of Philadelphia, Philadelphia, Pennsylvania (J.A.F.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/W17-0072 SectionsAboutVisual Abstract ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Video. Annals Story Slam - Just One More Question "Just One More Question," by Dr. Joel A. Fein (Duration 6:11)Building on the popular Annals feature “On Being a Doctor,” storytellers share stories about the experience of doctoring on video.For more videos from and information on Annals Story Slam, visit go.annals.org/StorySlam. Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (J.A.F.)Current Author Address: Joel A. Fein, MD, MPH; e-mail, [email protected]chop.edu. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 19 December 2017Volume 167, Issue 12Page: SS1 ePublished: 19 December 2017 Issue Published: 19 December 2017 Copyright & PermissionsCopyright © 2017 by American College of Physicians. All Rights Reserved.Loading ...
Association of polymorphisms of the inflammatory genes IL1B, COX-2 and IL1RN with increased risk of non-small cell lung cancer
Authors: Shanbeh Zienolddiny, Helge Lind, Daniele Campa, David Ryberg, Vidar Skaug, Valentina Maggini, Federico Canzian, Aage Haugen
Journal: Cancer Research (2004)

5297  Studies have indicated that inflammation and reactive oxygen species induced by smoking, may play a role in lung cancer development. The aim of this study was to investigate whether germline sequence variants of the inflammatory genes Interleukin-1B (IL-1B), interleukin 1 receptor antagonist (IL1RN), interleukin-6 (IL6), interleukin-8 (IL8), cyclooxygenase-2 (COX2/PTGS2), and the anti-inflammatory nuclear transcription factor PPARG act as common, low-penetrance alleles for susceptibility to lung cancer. In a case-control study, comprising of 523 individuals of Norwegian origin, the relative risk of lung cancer associated with allelic variants of these genes (SNPs) was determined using the TaqMan methodology. Here we report that carriers of IL-1B-31 (T/T) and IL-1B-511 (C/C) had increased risk of lung cancer with odds ratio of 2.39 (95% CI, 1.29-4.44) for –31T/T and 2.51 (95% CI, 1.47-4.58) for –511C/C genotypes. This risk was further increased by presence of an IL1RN-1 allele in combination with IL-1B T/T, odds ratio 5.7 (95% CI, 2.1-15.7) or IL-1B C/C; odds ratio 6.3 (95% CI, 2.3-17.1), respectively. Interestingly, the risk was completely abolished by presence of an IL1RN-2 allele in these subjects. In view of the significance of the p53 gene in lung carcinogenesis, we also analysed the IL1B genotypes in relation to p53 mutations in the tumors. The results indicated that subjects having homozygote genotypes were more likely to have a mutation in the p53 gene (P = 0.05). We also found that carriers of the C allele of a polymorphism in the 3’ UTR region of the COX2 gene had a significantly increased risk of lung cancer, with odds ratios of 4.28 (95% CI: 2.44-7.49) for homozygotes and 2.12 (95% CI: 1.25-3.59) for heterozygotes. It was also found that an IL6 promoter polymorphism was associated with increased risk of squamous cell carcinoma. In conclusion, we have demonstrated that polymorphisms in inflammatory genes may be associated with risk of lung cancer.