tbuckley/cabot-search huggingface dataset:
Emergency department-mediated cancer diagnosis among older adults in the United States.
Authors: Paige Sheridan, Georgios Lyratzopoulos, James Don Murphy, Caroline A. Thompson
Journal: Journal of Clinical Oncology (2019)

139 Background: It is estimated that 20-50% of breast, colon and lung cancers are diagnosed in an emergency department (ED) globally. Cancer diagnosis via the ED worsens short-term survival and reduces quality of care. Studies in Europe have shown that older and socioeconomically deprived patients are at a higher risk of ED diagnosis. However, no studies in the U.S. have reported patterns of cancer patients initially presenting to the ED. We identified and characterized older patients who are diagnosed with a malignant tumor following presentation to an ED using data from the Surveillance, Epidemiology and End Results Medicare linked database. Methods: We studied 415,395 Medicare beneficiaries with histologically confirmed first malignant invasive tumors of the breast, colon and rectum, lung and prostate between 2004 and 2013. Patients were excluded if they did not have continuous coverage in the year prior to diagnosis, had more than one primary tumor, or were diagnosed after death. ED-mediated diagnosis was defined as having at least one ED claim in the month before the date of cancer diagnosis. Covariate adjusted generalized linear models were used to estimate prevalence odds ratios for marital status, race, comorbidity, and income levels. Results: Overall, 42,186 (11%) of cancer diagnoses were ED-mediated (by site: breast: 5%, colorectal: 13%, lung: 15%, prostate: 6%). Patients presenting to the ED were more likely to be: unmarried (OR:1.32; 95% CI: 1.29-1.34), Hispanic (OR:1.47; 95% CI: 1.37-1.57) or Black (OR:1.41; 95% CI:1.37-1.45), have 3+ comorbidities (OR:3.08; 95% CI: 3.00-3.16), and in the lowest income quartile (OR:1.26; 95% CI:1.21-1.30). Conclusions: While some cancers diagnosed in the ED may indicate incidental findings, later stage symptomatic cancers not identified until they become an emergency may reflect the failure of public health campaigns and primary care services. Reducing emergency presentation of cancer patients may improve patient outcomes and healthcare system efficiency.
PNH Clone Size By Flow Cytometry and Its Correlation with PIG Gene Mutation
Authors: Dajeong Jeong, Hee Sue Park, Seongmin Choi, Heewon Seo, Sung-Min Kim, Kyongok Im, Jiwon Yun, Jung-Ah Kim, Sang Mee Hwang, Kwangsoo Kim, Ju Han Kim, Dong Soon Lee
Journal: Blood (2018)
Abstract 731: Sorafenib Induces Cardiotoxicity via Damage to Cardiac Endothelial Cells
Authors: Manar Elmadani, Zoltan Szabo, Sami Raatikainen, Lin Ruizhu, Tarja Alakoski, Jarkko Piuhola, Raisa Yrjolä, Ilkka Miinalainen, Pirjo Åström, Kari Alitalo, Olli Tehunen, Johanna Magga, Risto Kerkelä
Journal: Circulation Research (2019)

Aim: Sorafenib (Nexavar) is a multitargeted tyrosine kinase inhibitor that is used for treatment of hepatocellular carcinoma and renal cell carcinoma. Cancer treatment with sorafenib has been reported to be associated with cardiotoxic side effects such as hypertension, myocardial ischemia, thrombosis and pulmonary embolism, whereas incidence of LV dysfunction is rare. Aim of the current study was to identify the mechanism of sorafenib cardiotoxicity. Results: Healthy mice were treated with sorafenib (50 mg/kg/d) for 4 weeks. Echocardiography analysis revealed no difference in LV systolic function, but LV posterior wall thickness and relative wall thickness were significantly increased, and LV volume decreased in sorafenib treated mice. Hearts of sorafenib treated mice showed a 10-fold increase in expression of heart failure marker gene ANP and a 3-fold increase in the number of apoptotic cells. Electron microscopy analysis indicated damage to cardiac endothelial cells with no evidence of cardiomyocyte loss and co-staining of cardiac sections with endothelial marker CD31 revealed that ~80% of apoptotic cells in sorafenib treated hearts were endothelial cells (ECs). To assess for the time course for EC damage, we treated mice with sorafenib for 8h, 24h, 48h and 72h. The increase in EC death was already detected after 8h treatment and peaking at 24h-48h. RNA profiling analysis showed that expression of angiopoietin-1 (Angpt1) was reduced, whereas expression of Angpt2 was induced in hearts of mice treated with sorafenib for 4 weeks and in EC fractions from hearts of mice treated with sorafenib for 72h. Angpt-1 overexpression induced protective signaling pathways in hearts of mice treated with sorafenib for 48h, but did not rescue from acute EC injury. Treatment of Angpt1 overexpressing mice with sorafenib for 4 weeks resulted in capillary rarefaction and heart failure, evidenced by a decrease in LV systolic function and a 40-fold increase in ANP expression. Conclusion: our data shows that sorafenib cardiotoxicity is due to endothelial cell damage in the heart and results in heart failure with preserved ejection fraction. Furthermore, antagonizing the function of Angpt2 by overexpression of Angpt1 is detrimental during sorafenib treatment.
Abstract 827: Single-cell Transcriptomic Profiling Provides Insights Into Disease-related Processes During Hypertrophic Cardiomyopathy
Authors: Joep Eding, Maya Wright Clark, Anne de Leeuw, Bas Molenaar, Aryan Vink, Michelle Michels, Jolanda van der Velden, Eva van Rooij
Journal: Circulation Research (2019)

Hypertrophic cardiomyopathy (HCM) is a genetic disease usually caused by a heterozygous mutation in a sarcomeric gene. Histologically, HCM is characterized by a heterogeneous population of hypertrophic, disorganized cardiomyocytes and fibrosis of heart tissue. This hypertrophic growth can lead to outflow tract obstruction which can ultimately lead to progressive heart failure due to cardiac overload. Here we use single-cell RNA sequencing (scRNA-Seq) on septal myectomy samples from patients suffering from HCM to interrogate cellular heterogeneity in disease context. Using our previously optimized digestion and sorting protocol we were able to obtain good quality RNA for single cell analysis. Bioinformatic clustering analysis of single cell transcriptomes revealed 8 transcriptomically distinct subpopulations of cardiomyocytes. Our data indicate an NPPA/NPPB enriched cluster of cells and show TTN to function as an important determinant of the cellular heterogeneity. Correlation analysis links TTN expression to the expression of, among others, cardiomyopathy-associated protein (CMYA) 5 and 3, while there appears to be a negative correlation with, among others, TMEM212. We were able to confirm these correlations by RT-PCR on bulk RNA in an additional cohort of 97 HCM myectomy samples. Additionally, immuno-histochemical staining on myectomy samples and explanted HCM hearts confirmed the transcriptional heterogeneity among cardiomyocytes. A unique advantage of FACS-based single cell sorting cardiomyocytes is the availability of index data for the sorted cells. Correlation analysis of forward scatter, as a proxy for cell size, confirmed both well-known stress markers MYL2 and MYL7 and additional genes to be upregulated in the larger cells. In summary, we show that FACS-based sorting of HCM cardiomyocytes allows for scRNA-Seq of intact cardiomyocytes. Initial analyses of the data could be validated in a wider cohort of comparable samples, showing reliability of the data. Finally, incorporation of index data reveals genes correlated with cell size. Further interrogation of this data has the potential to reveal novel insights into the pathogenesis of HCM.
Chemokines CCL14 and CCL3 Facilitate Monocytes/Macrophage Infiltration in Multiple Myeloma Bone Marrow
Authors: Yi Li, Yuhuan Zheng, Li Yang, Qiang Wang, Enguang Bi, Tianshu Li, Yong Lu, Jianfei Qian, Mingjun Zhang, Maojie Yang, Qing Yi, Zhen Cai
Journal: Blood (2014)
Genome-Wide Analysis of Primary Plasma-Cell Leukemia Identifies Recurrent Imbalances Associated with Transcriptional Profile Alterations
Authors: Laura Mosca, Pellegrino Musto, Katia Todoerti, Marta Lionetti, Luca Agnelli, Giacomo Tuana, Sonia Fabris, Francesca Gaia Rossi, Vitina Grieco, Gabriella Bianchino, Fiorella D'Auria, Maria Teresa Petrucci, Fortunato Morabito, Francesco Nobile, Massimo Offidani, Francesco Di Raimondo, Nicola Cascavilla, Nunzio Filardi, Tommaso Caravita, Paola Omedè, Antonio Palumbo, Antonino Neri
Journal: Blood (2011)
ATRX In-Frame Fusion Neuroblastoma Is Sensitive to EZH2 Inhibition via Modulation of Neuronal Gene Signatures
Authors: Zulekha A. Qadeer, David Valle-Garcia, Dan Hasson, Zhen Sun, April Cook, Christie Nguyen, Aroa Soriano, Anqi Ma, Lyra M. Griffiths, Maged Zeineldin, Dan Filipescu, Luz Jubierre, Asif Chowdhury, Orla Deevy, Xiang Chen, David B. Finkelstein, Armita Bahrami, Elizabeth Stewart, Sara Federico, Soledad Gallego, Fumiko Dekio, Mary Fowkes, David Meni, John M. Maris, William A. Weiss, Stephen S. Roberts, Nai-Kong V. Cheung, Jian Jin, Miguel F. Segura, Michael A. Dyer, Emily Bernstein
Journal: Cancer Cell (2019)
WT-1 Expression Level In BM Is The Great Prognostic Marker In Three Of Classification IPSS, WPSS, and Latest Revised IPSS(IPSS-R)
Authors: Sumiko Kobayashi, Yasunori Ueda, Mineo Kurokawa, Kiyoyuki Ogata, Hirohiko Shibayama, Nobuhiko Emi, Kensuke Usuki, Kazuma Ohyashiki, Keiya Ozawa, Yasushi Miyazaki, Akira Matsuda, Kaoru Tohyama, Kinuko Mitani, Tomoki Naoe, Haruo Sugiyama
Journal: Blood (2013)
Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation for Adult Patients with T-Cell Acute Lymphoblastic Leukemia: A Survey From the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT)
Authors: Xavier Cahu, Myriam Labopin, Sebastian Giebel, Gerard Socie, Dietrich Beelen, Renate Arnold, Mauricette Michallet, Noel Milpied, Gulsan Sucak, Gunhan Gurman, Slawomira Kyrcz-Krzemien, Jakob R. Passweg, Ibrahim Yakoub-Agha, Matthias Stelljes, Jordi Esteve, Mohamad Mohty
Journal: Blood (2012)
Circulating Activin-A Is Elevated in Patients with Thalassemia Major and Double Heterozygous Sickle-Cell/Beta-Thalassemia and Correlates with Markers of Hemolysis and Bone Mineral Density
Authors: Ersi Voskaridou, Dimitrios Christoulas, Maria Dimopoulou, Veroniki Komninaka, Maria Tsalkani, Athanasios Papatheodorou, Evangelos Terpos
Journal: Blood (2012)
Abstract 308: Role of Snf1-related Kinase as a Regulator of Chromatin Modifications and Dna-damage Response in Heart Injury
Authors: Paulina J Stanczyk, Zachary Zilber, Adam de Jesus, Hsiang-Chun Chang, Hossein Ardehali
Journal: Circulation Research (2019)

Introduction: Altered DNA damage response (DDR) can result in phenotypic changes that share features with age-associated pathological conditions, including metabolic and cardiovascular abnormalities. Snf1-related kinase (SNRK) is a serine/threonine kinase that belongs to the AMPK family. Our recent data demonstrates that SNRK expression is upregulated in heart failure (HF) and low energy states and that SNRK improves cardiac mitochondrial efficiency and cell survival. Here, we assessed the hypothesis that in response to stress, SNRK translocates to the nucleus where it modulates nuclear processes to enhance DNA repair and ultimately reduces cardiomyocyte death. Results: We first showed that the nuclear distribution of endogenous SNRK in cardiomyoblast is enhanced under low nutrient and oxidative stress. Next, we performed global phosphoproteomics analysis on cells with overexpression of wild type SNRK and mutant kinase-dead SNRK (D158A). We found significant increase of several phosphopeptides involved in nuclear processes, in particular in the regulation of chromatin remodeling and DDR. SNRK downregulation resulted in an increase in nucleus volume and heterochromatin content, with increased nuclear dysmorphia when subjected to oxidative stress. Despite having lower expression of DDR signal effectors p53 and Mdm2, these cells accumulated higher levels of pH2AX (DDR marker) and displayed higher cellular death after oxidative stress, consistent with increased DNA damage. Etoposide treatment in SNRK knockdown cells failed to induce p53 levels despite pH2AX accumulation. Additionally, pharmacological stabilization of p53 protein through nutlin-3A treatment did not increase p53 in SNRK knockdown cells. These findings suggest that SNRK regulates p53 expression, thereby acting as a new modulator of DDR. Conclusions: Our results demonstrate increased nuclear localization of SNRK under stress conditions, and that SNRK regulates phosphorylation of nuclear proteins involved in chromatin remodelling and DDR. Thus, SNRK may induce its pro-survival cardiac functions through regulation of chromatin architecture and enhancing DDR. Those novel findings can contribute to development of new therapies against HF.
Abstract 377: KLF15-TCF7L2-dependent Cardiac Transcriptional Reprogramming Induces Cardiomyocyte and Vascular Cell Remodeling in the Mammalian Heart
Authors: Claudia Noack, Lavanya Iyer, Norman Liaw, Eric Schoger, Eva Wagner, Kerstin Zuehlke, Enno Klussmann, Wolfram-Hubertus Zimmermann, Laura C Zelarayan
Journal: Circulation Research (2019)

Integrative biochemical and omic-based approaches have refined our understanding of how cells integrate the Wnt signal at the chromatin level to yield specific cellular responses. However, this aspect remains unexplored in the heart. Since Wnt/β-catenin signaling activation is a hallmark in pathological cardiac remodeling, we aimed to characterize the specific Wnt cardiac transcriptional network regulation, amenable to therapeutic intervention in the adult heart. In the adult heart, we found the transcription factor KLF15 occupying regulatory regions of tissue remodeling genes containing Wnt transcriptional activator, TCF7L2, binding sites, which are silenced in the healthy myocardium but are active during pathological remodeling. Supporting KLF15 repressive roles, its loss resulted in cardiac TCF7L2 activation, maladaptive reprograming and failure in vivo . We demonstrated that KLF15 possess transcriptional age-specific repressive functions controlling Wnt signaling, cardiomyocyte de-differentiation and vascular cell (VC) remodeling. Employing different transgenic mouse models we further identified a cooperative program inducing aberrant VC remodeling, caused by a reduction of KLF15 with a concomitant TCF7L2 activation in cardiomyocytes. Furthermore, we characterized a cardiac specific Wnt transcriptional inhibitory complex consisting of KLF15 directly interacting with β-catenin and TCF7L2 and identified the amino acids critical for these interactions. Next, using a CRISPR/Cas9-mediated approach we generated KLF15 knockout (KO) hESC lines differentiated into functional cardiomyocytes and used for engineering human myocardium (EHM) generation. KLF15 KO EHMs showed activation of TCF7L2-dependent transcription as well as impaired function in comparison to control lines, recapitulating the Klf15 KO mouse phenotype. Altogether, we uncover an exquisite evolutionary conserved cardiac specific regulation mediated by KLF15 on Wnt signaling in myocardium offering a basis for designing highly specific pharmacological intervention for controlling Wnt cardiac-specific gene activation to prevent irreversible heart failure. We also underscore the significance of KLF15-Wnt dynamics in VC remodeling of the adult heart.
Abstract 255: Novel Role for Free Fatty Acid Receptor 4 in Response to Pathologic Pressure Overload-Induced Heart Failure in Mice
Authors: Katherine A Murphy, Sonal S Joshi, Chastity L Healy, Katherine M Ernste, Brian A Harsch, Brandon M Wagner, Wei Huang, Brian C Jensen, Gregory C Shearer, Timothy D O'Connell
Journal: Circulation Research (2019)

Free fatty acid receptor 4 (Ffar4, GPR120) is a GPCR for long chain fatty acids, including omega-3 polyunsaturated fatty acids (ω3-PUFAs). Previously, we demonstrated that eicosapentaenoic acid (EPA), an ω3-PUFA, prevents interstitial fibrosis and contractile dysfunction in pressure overload heart failure (transverse aortic constriction, TAC), but EPA was not incorporated into cardiac myocytes or fibroblasts, the traditional mechanism of action. Therefore, we hypothesized that Ffar4 is necessary for the anti-fibrotic and cardioprotective effects of EPA. In fact, we previously found that in primary cardiac fibroblasts, Ffar4 was sufficient and necessary to prevent TGFβ1-induced fibrosis. Here, we were surprised to find that Ffar4 also has important ω3-independent effects in cardiac myocytes in vivo . In mice with systemic deletion of Ffar4 (Ffar4KO mice) on a standard, corn oil diet (no EPA supplementation), TAC induced significantly more cardiac hypertrophy and more systolic (ejection fraction) and diastolic dysfunction (E/A ratio), but without excess fibrosis after 4 weeks. Mechanistically, transcriptome analysis in cardiac myocytes 3 days post-TAC indicated a deficiency of transcription in Ffar4KO myocytes. Sorting based on gene ontology indicated that genes functionally categorized as cell death and inflammation, including ilrn1 , hmox1 , Il33 , and ptgs2 (cox2) were not induced in the Ffar4KO myocytes. Ffar4 also activates cytoplasmic phospholipase A2 (cPLA2) inducing the production of oxylipins, and systemic deletion of cPLA2 induces exaggerated hypertrophy during development and following TAC. TAC increased cPLA2 expression in WT, but not Ffar4KO cardiac myocytes and oxylipin production was reduced in Ffar4KO mice. Finally, we confirmed that Ffar4 is expressed in human heart and down-regulated in heart failure. In summary, our data identify a novel, ω3-independent cardioprotective role for Ffar4 in cardiac myocytes.
Inhibitory effect of oral feeding of pomegranate fruit extract on UVB-induced skin carcinogenesis in SKH-1 hairless mice
Authors: Farrukh Afaq, Mohammad Zaid, Naghma Khan, Deeba Syed, Jung-Mi Yun, Sami Sarfaraz, Yewseok Suh, Hasan Mukhtar
Journal: Cancer Research (2008)

1246  Preventive approaches advocated for skin cancer such as the use of sunscreens and wearing protective clothing have not yielded the desired decline in skin cancers diagnosed. For this reason, additional approaches are needed to more effectively prevent photocarcinogenesis through a process we call photochemoprevention such as with the use of dietary antioxidant substances. Consistent with this notion there has been considerable interest in the identification of natural non-toxic dietary agents that are capable of affording protection to skin from the adverse effects of solar ultraviolet B (UVB) radiation. Pomegranate (Punica granatum L) fruit possesses strong anti-oxidant, anti-inflammatory and anti-proliferative properties. We earlier reported that oral feeding of pomegranate fruit extract (PFE) inhibited both single and multiple UVB radiation-induced short-term biomarkers of photocarcinogenesis in SKH-1 hairless mouse skin. Here, we determined whether oral feeding of PFE can inhibit UVB-mediated skin tumorigenesis. We used a UVB initiation-promotion protocol in which the control mice were subjected to UVB exposure of 180 mJ/cm2, twice a week for thirty weeks. The experimental animals received the same exposure protocol but also received PFE (0.2% w/v) ad libitum in drinking water starting 14 days before UVB exposure and continuing till the termination of the experiment. Compared to non PFE-treated animals, oral feeding of PFE resulted in reduced skin cancer development when expressed in terms of percent of mice with tumors and tumor multiplicity. Tumor appearance in UVB alone group occurred at the 12th week, which was delayed by 3 weeks in mice that received PFE. This inhibitory trend persisted throughout the course of the experiment. Additional studies were performed to examine the associated mechanisms of these inhibitory effects. STAT3 and NF-κB are constitutively active in many human tumors and contribute to photocarcinogenesis. Oral feeding of PFE showed a significant decrease in the phosphorylation of STAT3 (Tyr705) and NF-κB/p65 (Ser536) in uninvolved-skin from tumor-bearing mice and skin tumors compared to non PFE-treated animals. We also found a concomitant decrease in the protein expressions of iNOS, and COX-2, which are potential downstream targets of STAT3 and NF-κB. Moreover, there was a decrease in the protein levels of HIF-1α in tumors of mice that received PFE. Since HIF-1α is associated with neovascularization, we next examined the expression of VEGF and CD31, and observed a significant decrease in their protein levels. These data suggest that PFE has the potential to protect against skin tumorigenesis in mouse model of photocarcinogenesis, at least in part, by modulating transcription factors STAT3, NF-κB and HIF-1α leading to decrease in inflammatory and angiogenic responses, and provide a molecular basis for its photochemopreventive effect.
Abstract 11819: Impact of Dynamic Changes of Elevated Bilirubin on Survival in Patients on Veno-Arterial Extracorporeal Life Support for Acute Circulatory Failure
Authors: Miriam I Freundt, Dirk Lunz, Alois Philipp, Leopold Rupprecht, Stephan Hirt, David Flitter, Christof Schmid, Assad Haneya
Journal: Circulation (2016)

Introduction: Veno- arterial extracorporeal life support (ECLS) is an established method to stabilize acute circulatory failure by providing immediate gas exchange and peripheral tissue perfusion. Parameters and data on when to ideally wean circulatory support are limited. Hypothesis: Bilirubin levels may serve as indicator for readiness to wean ECLS. The purpose of this study was to evaluate the impact of dynamic changes of elevated bilirubin levels on survival in a large patient population on ECLS. Methods: We reviewed 502 consecutive cases of ECLS from 2007 to 2015. Bilirubin levels were recorded before implantation and then daily until six days after explantation. Bilirubin levels were statistically correlated with the primary outcome parameter 30-day survival and the secondary outcome parameters successful weaning and non-survival on ECLS. A multivariate regression analysis was performed to identify independent risk factors. Boxplots were generated to visualize dynamic changes in bilirubin levels. Results: Reason for ECLS was cardiac arrest with ongoing resuscitation in 230 (45.8%), low cardiac output in 174 (34.7%) and inability to wean off cardiopulmonary bypass in 98 (19.5%) patients. 307 (61.2%) patients were weaned off ECLS, however, only 206 (41.0%) ultimately survived 30 days. Mean duration of ECLS was 3 (2-6) days, and survivors received significantly longer ECLS (5 vs 3 days, p &lt; 0.001 ). Survivors had significantly lower bilirubin levels initially and on day 1 ( p = 0.003 and p = 0.013 ). Bilirubin started to rise notably from day 2 in all patients. In survivors bilirubin levels had trended down on the day of ECLS explantation and stayed at an acceptable level. However, in weaned patients and nonsurvivors bilirubin levels remained above baseline or even continued to rise during the recorded period. Conclusion: Down trending bilirubin levels on ECLS indicate improved chances of survival and may warrant weaning off support in hemodynamically stable patients.
GM-CSF in inflammation
Authors: John A. Hamilton
Journal: The Journal of Experimental Medicine (2019)

Granulocyte–macrophage colony-stimulating factor (GM-CSF) has many more functions than its original in vitro identification as an inducer of granulocyte and macrophage development from progenitor cells. Key features of GM-CSF biology need to be defined better, such as the responding and producing cell types, its links with other mediators, its prosurvival versus activation/differentiation functions, and when it is relevant in pathology. Significant preclinical data have emerged from GM-CSF deletion/depletion approaches indicating that GM-CSF is a potential target in many inflammatory/autoimmune conditions. Clinical trials targeting GM-CSF or its receptor have shown encouraging efficacy and safety profiles, particularly in rheumatoid arthritis. This review provides an update on the above topics and current issues/questions surrounding GM-CSF biology.