tbuckley/cabot-search huggingface dataset:
Abstract 4643: Mutant ASXL1 collaborates with HHEX to promote myeloid leukemogenesis
Authors: Shuhei Asada, Reina Takeda, Daichi Inoue, Susumu Goyama, Toshio Kitamura
Journal: Cancer Research (2019)

Abstract An epigenetic modulator Additional sex combs-like 1 (ASXL1) is recurrently mutated in myeloid neoplasms and its mutations are associated with poor prognosis. Recently, we generated mutant Asxl1 conditional knock-in (Asxl1-MT KI) mice mimicking human ASXL1 E635RfsX15 mutation, one of the most common mutations in myeloid neoplasms (Nagase et al. JEM 2018). Retrovirus-mediated insertional mutagenesis study exhibited susceptibility of Asxl1-MT KI bone marrow cells to myeloid leukemia, and we identified Hematopoietically expressed homeobox (Hhex) gene as one of the common retrovirus integration sites. In this study, we investigated the potential cooperation between the mutant ASXL1 and HHEX in myeloid leukemogenesis. We first performed colony-forming assay and found that forced expression of HHEX enhanced colony replating activity and blocked myeloid differentiation in bone marrow hematopoietic stem progenitor cells (HSPCs) derived from ASXL1-MT KI mice, while it showed only modest effect in normal HSPCs. The synergistic effect between the mutant ASXL1 and HHEX in blocking myeloid differentiation was also observed in human HL-60 cells. We next evaluated the role of endogenous Hhex in the mutant ASXL1-expressing cells. Depletion of endogenous Hhex using CRISPR-Cas9 system ameliorated mutant ASXL1-induced differentiation block in 32Dcl3 cells. Depletion of endogenous Hhex in murine mutant ASXL1-expressing leukemia cells [cSAM cells: cells with combined expression of SETBP1 and ASXL1 mutations (Inoue et al. Leukemia 2015), cRAM cells: cells with combined expression of RUNX1 and ASXL1 mutations (Nagase et al. JEM 2018)] also promoted differentiation and increased apoptosis. Furthermore, Hhex deletion profoundly attenuated the colonogenicity of cSAM and cRAM cells and leukemogenicity of cSAM cells. We then investigated target genes of the mutant ASXL1 and HHEX in myeloid neoplasms using public database and our previous RNA-Seq data. Among the potential target genes of the mutant ASXL1 and HHEX, we found that Myb, Etv5 and Oraov1 genes were upregulated by the mutant ASXL1 and HHEX in murine HSPCs. Conversely, Hhex depletion resulted in downregulation of these genes both in cSAM and cRAM leukemic cells. In addition, depletion of Myb, Etv5 or Oraov1 genes significantly abrogated the colonogenicity of cSAM cells. These data suggest that mutant ASXL1 and HHEX cooperatively induce myeloid leukemogenesis via dysregulating Myb, Etv5 and Oraov1. Citation Format: Shuhei Asada, Reina Takeda, Daichi Inoue, Susumu Goyama, Toshio Kitamura. Mutant ASXL1 collaborates with HHEX to promote myeloid leukemogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4643.
Abstract 3701: Fn14 overexpression in RCAS/tv-a rat gliomas promotes tumor progression, increases invasion and decreases survival
Authors: Nina Connolly, Heather Ames, Nhan L. Tran, Anthony Kim, Jeff Winkles, Graeme Woodworth
Journal: Cancer Research (2019)

Abstract Fibroblast growth factor-inducible 14 (Fn14) is the cell surface receptor for the tumor necrosis factor (TNF) family member TNF-like weak inducer of apoptosis (TWEAK). The Fn14 gene is not normally expressed in healthy tissues, but expression is significantly increased in many primary solid tumor types, including glioblastoma (GBM). High Fn14 expression in tumors is often associated with the stimulation of cancer cell invasion leading to diffuse, aggressive tumors and metastasis. To investigate the effects of increased Fn14 expression in brain tumors, two different tumor types were developed using the RCAS/tv-a transgenic rat model: a low-Fn14, “proneural-like” (PDGFA/shP53 derived) tumor and a high-Fn14 (PDGFA/shP53/Fn14-derived) tumor. Interestingly, rats with high-Fn14 brain tumors had a significantly shorter median survival compared to those with low-Fn14 with 42 days and 70 days median survival, respectively. Using MR proton spectroscopy, both tumor types exhibited the markers of a malignant glioma such as increases in choline to creatinine ratio (Cho/Cr) and decreases in neuronal activity (NAA); however, high-Fn14 tumors also displayed an increase in lactate during tumor progression which is often a sign of high grade, necrotic tumors and poor prognosis. Morphologically, the two tumor subtypes appear quite different. H&amp;E staining of the high-Fn14 tumors showed a highly malignant tumor with several areas of pseudopalisading necrosis within the tumor core. This is different than the somewhat more homogeneous morphology of the low-Fn14 proneural-like tumor. The pattern of tumor cell invasion also differs between the two brain cancer subtypes. High-Fn14 tumors show a more human GBM-like pattern by invading along the white matter tracts whereas low-Fn14 tumors appear to invade more locally with minimal white matter invasion. High-Fn14 tumors were positive for Fn14 throughout the tumor including the invasive rim of the tumor, which is also seen in human GBM, whereas the low-Fn14 tumor revealed very little staining even at the invasive rim. These findings indicate that increased Fn14 expression creates a more malignant brain tumors that develops and behaves more aggressively then low-Fn14 tumors. Citation Format: Nina Connolly, Heather Ames, Nhan L. Tran, Anthony Kim, Jeff Winkles, Graeme Woodworth. Fn14 overexpression in RCAS/tv-a rat gliomas promotes tumor progression, increases invasion and decreases survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3701.
Abstract 239: Out-of-Hospital Cardiac Arrest Survival Predicted at 24 Hours: The Application and Validation of a Novel Clinical Score
Authors: Aiham Albaeni, Shaker M Eid, Dhananjay Vaidya, Nisha Chandra-Strobos
Journal: Circulation (2012)

Background : Despite 50 years of research, survival prognostication is still dependant on clinical status at 72 hours. We developed and tested the accuracy of a 24 hour, novel clinical score to predict the probability of survival post non-traumatic cardiac arrest. Methods : In 170 cardiac arrest survivors admitted between 2004-2010, a predictive model was developed. Variables used in univariate analyses to generate the prediction equation were: Initial Rhythm VF/VT, Return of Spontaneous Circulation (ROSC) ≤20 minutes, Brian Reflex Score (BRS)≥ 3 at 24 hours, Bystander CPR, and use of ≥3 doses of epinephrine. Multivariate logistic regression then retained significant predictors in a 50% random training sample, 84 patients (pts) and tested these in the remaining 50% validation sample, 86 pts. The diagnostic efficiency of the model was assessed using ROC analysis. Results : Of 170 pts studied, mean age was 63 years(SD±15.7), 37 pts (21.7%) survived to discharge. The initial rhythm was VF/VT in 38 (22%), 58 (34%) had ROSC≤ 20 minutes, 34 (20%) had a BRS ≥3 at 24 hours, and 80(47%) received Hypothermia. Mean length of stay was 5.8 days (SD±7.8).The final model retained three predictors: VF/VT, ROSC≤ 20 minutes and BRS≥ 3 at 24 hours. Table below presents the probability of survival with presence/ absence of all combinations of these 3 predictors. No single variable was robust in identifying the probability of survival (9%-17%). The presence of any 2 variables increases the probability to (55%-71%),however the presence of all 3 variables, in any patient increases the probability to 95%. The area under the ROC curve was 0.87 in the training sample and 0.84 in the validation sample. Conclusion : This study demonstrates that a score comprising 3 easily clinically, accessible variables correctly identifies survival following cardiac arrest. This score,like many other clinical scores, is incremental in predictive accuracy and warrant revalidation in larger cohort.
Abstract 15493: Microvesicle Injection Improves Myocardial Function and Increases Angiogenesis in a Swine Model of Chronic Ischemia
Authors: Brittany A Potz, Laura A Scrimgeour, Vasile I Pavlov, Neel R Sodha, Ruhul M Abid, Frank W Sellke
Journal: Circulation (2017)

Introduction: Mesenchymal stem cell derived microvesicles are cardio-protective in animal models of myocardial infarct. The objective of this study is to examine the effects of human mesenchymal ce...
Abstract 20707: Role of Il-10 in the Modulation of Oxidized Phospholipids During Ischemia/Reperfusion (i/r) Injury in the Heart
Authors: Ashim K Bagchi, Gauri Akolkar, Andrea Edel, Rakesh Chaudhary, Amir Ravandi, Pawan K Singal
Journal: Circulation (2017)

Oxidized phosphatidylcholines (OxPCs) have been shown to play a crucial role in pathophysiological response during inflammation. These OxPCs are also generated by cardiomyocytes during myocardial I...
Abstract 5144: The potential biomarkers and rational combination of immunotherapy in microsatellite stable colorectal cancer
Authors: Xuman Lu, Zhe Ji, Jing Zhao, Yuzi Zhang, Mengli Huang, Shangli Cai, Jun Huang
Journal: Cancer Research (2019)

Abstract Purpose Immune checkpoint blockades (ICBs) have been reported to be used in early stage colorectal cancer (CRC) as neoadjuvant therapy. However, it seems that microsatellite stable (MSS) CRC patients obtained no significant clinical benefit in studies with small sample size. We aimed to explore the potential biomarkers and rational immunotherapy to optimize response to ICBs in MSS CRC. Procedures Whole exome sequencing and RNAseq of 612 CRC patients from The Cancer Genome Atlas were analyzed. T cell dysfunction/exclusion signatures and Tumor infiltrating lymphocytes were calculated from TIDE model and TIMER algorithm, respectively. Mann Whitney U test and Kruskal test were used to compare the difference among two or more than two groups. P value was adjusted by BH method for multiple comparisons. Results There were 109 stage I, 228 stage II, 184 stage III and 91 stage IV in 612 CRC patients. The MSI-H prevalence, tumor mutation burden, PD-L1 mRNA and CD8 T cell infiltration decreased with the increase in pathologic stage (all P &amp;lt; 0.01). In MSS CRC, mRNA expression of immune checkpoint related genes including PD-L1, CTLA4 and LAG3 were significantly higher in stage I-III than stage IV (adjusted P &amp;lt; 0.01, &amp;lt; 0.01 and 0.04, respectively). For immune activation genes (CD8A, CXCL9, CXCL10, GBP1, GZMB, GZMA, IFNG, FAS, STAT1, TAP1), their mRNA expression levels increased with the decrease of stage (All adjusted P &amp;lt; 0.01). Besides, stage I-III MSS CRC had lower T cell exclusion signature score than stage IV (adjusted P = 0.02). No similar results were observed in MSI-H. Compared with MSI-H, MSS had higher M2 macrophage signature score (P &amp;lt; 0.001), but no association were observed between M2 macrophage signature and stage. Conclusions Early stage CRC with MSS had higher levels of positive predictive features for ICBs treatment, which suggested stronger immune responsiveness. Combination of M2 macrophage inhibitor and ICBs has the potential to turn “cold tumor” into “hot tumor” and acts as a promising therapeutic regimen, especially for early stage CRC. More clinical trials are needed to confirm this hypothesis. Note: This abstract was not presented at the meeting. Citation Format: Xuman Lu, Zhe Ji, Jing Zhao, Yuzi Zhang, Mengli Huang, Shangli Cai, Jun Huang. The potential biomarkers and rational combination of immunotherapy in microsatellite stable colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5144.
Abstract LB-209: Novel pathway prediction for colorectal cancer to liver metastasis through bioinformatics
Authors: Precious Takondwa Makondi, Chien-Yu Huang, Yu-Jia Chang
Journal: Cancer Research (2019)

Abstract Background: Liver metastases are the most common cause of colorectal cancer (CRC) related deaths, with no reliable clinical predictors. Therefore, identifying potential candidate predictors is crucial for clinical application and management. Methodology: The Gene Expression Omnibus (GEO) datasets GSE49355, GSE41258 and GSE81558 for genes and GSE54088 and GSE56350 for miRNAs were used to identify common differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs) between paired primary CRC tissues and the corresponding liver metastatic tissues. Then, DEMs targets were identified from DEGs. These were verified in GEO datasets comprising gene, miRNA and miRNA exosome profiles of CRC patients with no distant metastases (M0) and distant metastases (M1); the interaction networks and pathways were also mapped. Results: There were 49 upregulated and 13 downregulated DEGs, and 16 downregulated and 14 upregulated DEMs; between DEGs and DEMs targets, there were five upregulated and four downregulated genes. MiR-20a was significantly high in M1, with the combination of MiR-20a, -495, -576-5p and -449a offering a superior prediction value (sensitivity of 83.3%, specificity of 63.8%, AUC of 0.725). In miRNA exosomes, MiR-576-5p was significantly low in M1, while MiR-20a and -449a were highly expressed, and combination of miR-20a, -495, -576-5p, -449a, -619 and -382 provided best predictive value (sensitivity=75.0%, specificity=88.2%, AUC=0.875). The miRNA target CDH2 was significantly highly expressed in M1 while KNG1 and MMP2 were lowly expressed. The miRNA to gene interaction model was demonstrated, and enriched pathways were; regulation of IGF transport and uptake by IGFBPs, extracellular matrix organization, signal transduction and immune system. Conclusion: This model predicts novel pathway for predicting CRC to liver metastases. This may be clinically applicable. Citation Format: Precious Takondwa Makondi, Chien-Yu Huang, Yu-Jia Chang. Novel pathway prediction for colorectal cancer to liver metastasis through bioinformatics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-209.
Medicine, Money and Manpower — The Challenge to Professional Education
Authors: Ward Darley, Anne R. Somers
Journal: New England Journal of Medicine (1967)

UNTIL recently, many of the shortcomings of American medicine could be blamed on inadequate financing. Education for the health professions, the distribution of medical care and even medical research were all grossly underfinanced in relation both to the health needs of the American people and to the potential inherent in twentieth-century scientific advance. Just a little over a decade ago the late Dr. Alan Gregg spoke for a host of farsighted professionals and consumers alike when he lashed out against the "cribbed, cabined, and confined" conditions of American medicine.1 As far as the availability of money is concerned, this situation . . .
The Rate of Change of Left Ventricular Volume in Man
Authors: K. E. HAMMERMEISTER, J. R. WARBASSE
Journal: Circulation (1974)

Because there is little quantitative information about the hemodynamics of left ventricular diastolic events in man, single-plane cineangiographic left ventricular volume curves were quantitatively analyzed at 16.6 msec intervals to evaluate the rate and amount of left ventricular filling during the early passive stage of filling and during the time of atrial contraction. The peak rate of passive diastolic filling of the left ventricle (D dV/dt), the peak rate of filling during atrial contraction (dV/dt c 'a'), and the increment in diastolic left ventricular volume due to atrial contraction (ΔV c 'a') were analyzed for a group of 110 adult patients with a variety of cardiac lesions. Normal D dV/dt, 503 ± 171 cc/sec, was significantly depressed in patients with mitral stenosis (393 ± 109 cc/sec) and coronary artery disease (394 ± 150 cc/sec). When corrected for end-diastolic volume (EDV), the resultant D dV/dt/EDV was significantly depressed in all disease states studied. D dV/dt corrected similarly for total left ventricular stroke volume (SV) was depressed from normal in patients with coronary disease, mitral stenosis, and valvular regurgitation. These data indicate that patients with coronary disease and chronic valvular disease have an abnormality in early diastolic filling of the left ventricle and that this may have a more profound effect on ventricular performance than changes in late diastolic compliance. D dV/dt has a high correlation with peak systolic ejection rate ( r = 0.71), SV ( r = 0.82), and EDV ( r = 0.51). The normal ΔV c 'a' represents 21% of the stroke volume (16% of the stroke volume if corrected for passive filling during this time period). Patients with coronary artery disease, valvular regurgitation, and aortic stenosis have an increased ΔV c'a'. Atrial contraction results in a second peak in mitral valve flow in late diastole (dV/dt c 'a'). In normal patients dV/dt c 'a' is 38% of D dV/dt, but in disease states this ratio is substantially increased. In the diseased heart atrial contraction makes a greater contribution to cardiac output than in the normal heart.
Abstract 309: Long-Term Therapy with Ivabradine Increases ACE-2 Activity in Left Ventricular Myocardium of Dogs with Chronic Heart Failure
Authors: Ramesh C Gupta, Mengjun Wang, Sharad Rastogi, Keife Zhang, Hani N Sabbah
Journal: Circulation Research (2012)

Background: Angiotensin converting enzyme 2 (ACE2) is a homolog of ACE. ACE2 removes the terminal amino-acid from angiotensin-II (Ang II) to form Ang(1-7) which antagonizes the effects of Ang-II by activating the Mas receptor. We showed that ivabradine (IVA), a novel inhibitor of the cardiac pacemaker current I f , improves left ventricular (LV) function and prevents progressive LV remodeling in dogs with microembolization-induced heart failure (HF). Because RAAS system overactivity contributes to the progression of HF, we assessed changes in Ang-II level and ACE and ACE2 activity in LV of dogs treated with IVA. Methods: Studies were performed in LV tissue from 24 HF dogs randomized to 3 months therapy with high dose (HD) IVA (30 mg twice daily, n=8), low dose (LD) IVA (15 mg twice daily, n=8) or to no therapy at all (Control, CON, n=8). LV tissue from 6 normal (NL) dogs was used for comparison. A fluorogenic peptide, captopril (ACE inhibitor) and DX600 (ACE2 inhibitor) were used to quantify the activity of ACE and ACE2 in LV homogenate. Activity was expressed as fluorescence unit (FU)/μ g protein/hour. Ang II level was determined by ELISA. Results: IVA reduced heart rate (HR) and significantly increased LV ejection fraction in a dose-dependent manner. Ang II level and ACE and ACE2 activities were up-regulated in HF CON compared to NL dogs. Compared to CON, treatment with IVA reduced ACE activity and Ang II level but increased ACE2 activity in a dose-dependent manner (Table). Conclusions: In dogs with HF, therapy with IVA reduces activation of ACE and Ang II level but increases activation of ACE2. The latter may contribute to the observed beneficial effects of IVA on LV function and remodeling in HF.
Blood eosinophils and treatment response with triple and dual combination therapy in chronic obstructive pulmonary disease: analysis of the IMPACT trial
Authors: Steven Pascoe, Neil Barnes, Guy Brusselle, Chris Compton, Gerard J Criner, Mark T Dransfield, David M G Halpin, MeiLan K Han, Benjamin Hartley, Peter Lange, Sally Lettis, David A Lipson, David A Lomas, Fernando J Martinez, Alberto Papi, Nicolas Roche, Ralf J P van der Valk, Robert Wise, Dave Singh
Journal: The Lancet Respiratory Medicine (2019)
Shackled at the End of Life: We Can Do Better
Authors: Michele DiTomas, Joseph Bick, Brie Williams
Journal: The American Journal of Bioethics (2019)

Between 1993 and 2013, the number of state prison inmates in this country who are age 55 years or older increased approximately fourfold. Nearly 1 in 10 individuals incarcerated in U.S. prisons is ...
Construction of multiple visual analog scale (UAD‐9) for measuring severity of symptoms and quality of life of patients with respiratory allergy
Authors: Norbert Lukan, Peter Kolarcik, Veronika Benetinova, Tibor Varga
Journal: Allergy (2019)

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Neutrophil extracellular traps and low-density granulocytes are associated with the interferon signature in systemic lupus erythematosus, but not in antiphospholipid syndrome
Authors: Lucas L van den Hoogen, Maarten van der Linden, Linde Meyaard, Ruth D E Fritsch-Stork, Joel A van Roon, Timothy RDJ Radstake
Journal: Annals of the Rheumatic Diseases (2019)

With great interest we read the article by Rahman et al 1 about the clinical associations and functional characteristics of low-density granulocytes (LDGs) in patients with systemic lupus erythematosus (SLE).

LDGs are a subset of proinflammatory neutrophils which numbers are increased in patients with SLE as well as other rheumatic diseases including antineutrophil cytoplasmic antibody-associated vasculitis, rheumatoid arthritis and antiphospholipid syndrome (APS).2–5 LDGs are proposed to be involved in the pathogenesis of rheumatic diseases by spontaneously releasing neutrophil extracellular traps (NETs).5 6 NETs consist of web-like structures of chromatin decorated with antimicrobial and other neutrophil-derived peptides. NETs induce vascular damage,6 thrombosis7 and are a source of autoantigens5 to trigger autoimmunity and thus could contribute to the pathogenesis of autoimmune diseases.

Arguably, the most important contribution of NET release to the pathogenesis of SLE is their effect on plasmacytoid dendritic cells (pDCs). In vitro, NETs trigger toll-like receptors on pDCs resulting in the production of interferon alpha (IFNα).6 8 9 In turn, IFNα primes neutrophils to release NETs8 9 resulting in a perpetuating pathogenic cycle of NET release and IFNα production. Elevated levels …
Positive Predictive Values and Potential Success of Suicide Prediction Models
Authors: Gregory E. Simon, Susan M. Shortreed, R. Yates Coley
Journal: JAMA Psychiatry (2019)

To the Editor We write to disagree with the pessimism of Belsher et al1 regarding the potential utility of models predicting suicidal behavior. They argue that no existing models have positive predictive value high enough to guide prevention efforts.