tbuckley/cabot-search huggingface dataset:
Abstract 20296: In-Hospital Outcomes for Type A Acute Aortic Dissection Patients Presenting With Abnormal Admission Electrocardiogram
Authors: Nathaniel Costin, Amit Korach, Gabriel Loor, Mark D Peterson, Nimesh D Desai, Santi Trimarchi, Takeyoshi Ota, T B Reece, Thoralf M Sundt, Himanshu J Patel, Edward P Chen, Daniel G Montgomery, Christoph A Nienaber, Eric M Isselbacher, Kim A Eagle, Thomas G Gleason
Journal: Circulation (2016)

Introduction:  Electrocardiogram (ECG) is often used to assist in the diagnosis of patients presenting with chest pain to emergency departments. Given that this type of pain is a common manifestation of Type A Acute Aortic Dissection (TAAAD), ECGs are obtained in much of this population. This study evaluated the impact of particular ECG patterns on the diagnosis and treatment of TAAAD.   Methods:  TAAAD patients (N=2765) enrolled in the International Registry of Acute Aortic Dissection were stratified into groups based on normal (N=1094, 39.6%) and abnormal (N=1671, 60.4%) presenting ECGs, and further subdivided according to specific ECG findings. Time data is presented in hours as medians (Q1-Q3).   Results:  Patients with abnormal ECG findings presented to the hospital sooner after symptom onset than those with normal ECGs (1.4 (0.8-3.3) v 2.0 (1.0-3.3); p=0.005). Specifically, shorter time from symptom onset to presentation was seen in patients with infarction with new Qs or ST elevation (1.3 (0.6-2.7) v 1.5 (0.8-3.3); p=0.049). Abnormal ECG findings were associated with less frequent surgical management (84.7% v 92.8%; p   Conclusions:  An abnormal ECG in patients with TAAAD remains an adverse prognosticator identifying a group of patients who are sicker, have more in-hospital complications, and are more likely to die. That nonspecific ST-T abnormalities are seen in more than 40% of TAAAD patients are associated with a delay in diagnosis and treatment suggests that this is an area for further study.
Race Disparities in the Contribution of miRNA Isoforms and tRNA-Derived Fragments to Triple-Negative Breast Cancer
Authors: Aristeidis G. Telonis, Isidore Rigoutsos
Journal: Cancer Research (2017)

Abstract Triple-negative breast cancer (TNBC) is a breast cancer subtype characterized by marked differences between White and Black/African-American women. We performed a systems-level analysis on datasets from The Cancer Genome Atlas to elucidate how the expression patterns of mRNAs are shaped by regulatory noncoding RNAs (ncRNA). Specifically, we studied isomiRs, that is, isoforms of miRNAs, and tRNA-derived fragments (tRF). In normal breast tissue, we observed a marked cohesiveness in both the ncRNA and mRNA layers and the associations between them. This cohesiveness was widely disrupted in TNBC. Many mRNAs become either differentially expressed or differentially wired between normal breast and TNBC in tandem with isomiR or tRF dysregulation. The affected pathways included energy metabolism, cell signaling, and immune responses. Within TNBC, the wiring of the affected pathways with isomiRs and tRFs differed in each race. Multiple isomiRs and tRFs arising from specific miRNA loci (e.g., miR-200c, miR-21, the miR-17/92 cluster, the miR-183/96/182 cluster) and from specific tRNA loci (e.g., the nuclear tRNAGly and tRNALeu, the mitochondrial tRNAVal and tRNAPro) were strongly associated with the observed race disparities in TNBC. We highlight the race-specific aspects of transcriptome wiring by discussing in detail the metastasis-related MAPK and the Wnt/β-catenin signaling pathways, two of the many key pathways that were found differentially wired. In conclusion, by employing a data- and knowledge-driven approach, we comprehensively analyzed the normal and cancer transcriptomes to uncover novel key contributors to the race-based disparities of TNBC. Significance: This big data-driven study comparing normal and cancer transcriptomes uncovers RNA expression differences between Caucasian and African-American patients with triple-negative breast cancer that might help explain disparities in incidence and aggressive character. Cancer Res; 78(5); 1140–54. ©2017 AACR.
Efficacy of lentivirus-mediated gene therapy in an Omenn syndrome recombination-activating gene 2 mouse model is not hindered by inflammation and immune dysregulation
Authors: Valentina Capo, Maria Carmina Castiello, Elena Fontana, Sara Penna, Marita Bosticardo, Elena Draghici, Luigi P. Poliani, Lucia Sergi Sergi, Rosita Rigoni, Barbara Cassani, Monica Zanussi, Paola Carrera, Paolo Uva, Kerry Dobbs, Nicolò Sacchetti, Luigi D. Notarangelo, Niek P. van Til, Gerard Wagemaker, Anna Villa
Journal: Journal of Allergy and Clinical Immunology (2017)
Abstract 19475: Cardiovascular Burden in Children With Chronic Kidney Disease
Authors: Shriprasad Deshpande, Stephanie Eick, Pamela D Winterberg
Journal: Circulation (2015)

Introduction: Cardiovascular disease is the leading cause of death in children and young adults with chronic kidney disease (CKD) and kidney transplant. Phenotype of cardiac involvement may be variable. In adults with CKD, diastolic dysfunction has been shown to be an independent risk factor for mortality. However, there is overall very limited data in pediatric age group. Additionally, there are no guidelines for appropriate screening, assessment or standardized follow-up for cardiac pathology in pediatric CKD. The purpose of this study is to assess the overall cardiovascular burden and more specifically, diastolic dysfunction (DD) in pediatric CKD patients. Methods: Single center, retrospective cohort study of patients seen for CKD. Results: 237 patients with CKD /ESRD were identified including 64 patients who underwent renal transplant and 84 on chronic dialysis. Mean age was 14 years (7.6 to 17.5). Systolic hypertension was present in 49.7% while diastolic hypertension in 36.1%. 22% had a BMI greater than 95% percentile. Echocardiographic assessment showed preserved systolic function in majority (mean ejection fraction of 67.8%, range 19-90%). However, LV mass index(LVMI) was &gt; 38 g/m2.7 in 66% (115/173). Tissue Doppler velocities demonstrated a large variation with significant abnormalities indicating abnormal myocardial performance and diastolic dysfunction. Mitral e velocity which was diminished in 79% while severely diminished in 31%. Mitral a,s and E/e’ velocities were abnormal in varying portion of population. Relative wall thickness was significantly increased (&gt;0.41) in 112/213 patients. Serial measures showed a gradual increase in E/e’ ratio mean from 8.1 to 9.9 and increase in LVMI from mean of 44.5 to 53.1 g/m2.7 (p&lt;0.05). Conclusion: This is the largest study to date of demonstrating a significant cardiovascular burden in patients with CKD in the form of hypertrophy as well as abnormalities of myocardial performance and diastolic function. Serial measures show the parameters correlate with disease state. Further analysis in underway to identify risk factors and propose guidelines for serial screening.
Abstract 14004: Role of Inflammation in the Pathogenesis of Hypertension a 9-year Repeated-measures Data Analysis in a Prospective Cohort Study
Authors: Hirofumi Tomiyama, Chisa Matsumoto, Shunsuke Komatsu, Kazutaka Kimura, Kazuki Shiina, Akira Yamashina
Journal: Circulation (2016)

Introduction: The underlying mechanisms of the association of inflammation with the development of hypertension has not been clarified. Hypothesis: Inflammation affect the development of hypertension via vascular and/or renal abnormalities. Methods: The association of inflammation with vascular and/or renal abnormalities, and the association of such abnormalities with elevation of the blood pressure were examined by analyzing longitudinal repeated-measures data using a linear mixed model (LMM) approach in a 9-year prospective observational study. 3908 middle-aged Japanese employees of the construction company (aged 41 ± 9 years old) without hypertension at the study baseline. The blood pressure, brachial-ankle pulse wave velocity (baPWV), radial augmentation index (rAI), estimated glomerular filtration rate (eGFR; based on the serum creatinine) and serum C-reactive protein (CRP) levels were measured annually in the subjects from year 2007 to year 2015. Results: During this study period, 520 subjects (13%) developed hypertension. LMM analysis of the obtained repeated-measures data after adjustments for covariates revealed the following: 1) At each annual measurement, higher annual values of the log-transformed CRP were associated with a higher annual increase of the baPWV (beta = 62.647 ± 26.017, p &lt; 0.001), but not the annual increase of the rAI or annual decrease of the eGFR; 2) higher annual values of the baPWV were associated with a higher annual elevation of the blood pressure (beta = 0.032 ± 0.001, p &lt; 0.001). Conclusions: In middle-aged Japanese subjects without hypertension at the study baseline, the presence of inflammation, as reflected by serum CRP levels, appears to be associated with the longitudinal increase of the arterial stiffness, but not with abnormal progression of the central hemodynamics or decline of the glomerular filtration rate. In turn, this longitudinal increase in the arterial stiffness appears to be associated with the longitudinal elevation of the blood pressure to hypertensive range. Thus, inflammation may play a role in the pathogenesis of hypertension via the accelerated progression of arterial stiffness.
Abstract O.25: Identification Of Pathogenic Cardiac Cd11c+ Macrophages In Nod1-mediated Coronary Arteritis, A Murine Model Of Kawasaki Disease
Authors: Yoshitomo Motomura, Shunsuke Kanno, Hisanori Nishio, Toshiro Hara, Sho Yamasaki
Journal: Circulation (2015)

Kawasaki disease is characterized by granulomatous inflammation of coronary arteries. We previously reported that a synthetic Nod1 ligand FK565 induced coronary arteritis in mice similar to that of Kawasaki disease. However, the molecular mechanism underlying this site-specific vasculitis has remained elusive. We found that CD11c+ MHC class II+ cells were accumulated in heart of FK565-treated mice prior to arteritis development, which was abolished in Nod1-/- mice. In vivo depletion of mononuclear phagocytes or CD11c+ cells prevented the arteritis, whereas elimination of T cells, B cells, NK cells, and neutrophils did not alter the pathology. Morphological features and gene expression signature of the cardiac CD11c+ MHC class II+ cells suggested that this population was closely related to macrophages. Notably, various inflammatory cytokines, chemokines, lysosomes and MMPs were expressed in these cardiac CD11c+ macrophages, suggesting that this population contributed to tissue destruction. Next, we determined whether Nod1 in hematopoietic cells or non-hematopoietic cells were important for this arteritis. Bone marrow chimera mice using WT and Nod1-/- mice indicated that Nod1 in non-hematopoietic host cells, rather than in hematopoietic cells, was important for the accumulation of the cardiac CD11c+ macrophages and arteritis development. Among non-hamatopoietic cells, cardiac endothelial cells abundantly produced chemokines in response to FK565. In this respect, CCR2-deficient mice exhibited decreased cardiac CD11c+ macrophages and compromised inflammation. These results suggested that Nod1 activation in endothelial cells triggers accumulation of cardiac CD11c+ macrophages, which is a prerequisite for the development of coronary arteritis.
Twin Pregnancy With Gestational Diabetes Mellitus: A Double Whammy?
Authors: Sara Ooi, Vincent W. Wong
Journal: Diabetes Care (2017)

Twin pregnancies represent 1.5% of all pregnancies in Australia, and they have an increased risk of gestational diabetes mellitus (GDM). Singleton GDM and twin pregnancies both represent high-risk pregnancies, but optimal management of twin GDM pregnancies is not clearly defined.

Between 2011 and 2015, 410 women with twin pregnancies gave birth at our institution, and 99 (24.1%) developed GDM during their pregnancy. In the same period, there were 2,639 singleton pregnancies complicated by GDM. GDM was diagnosed by the 75-g oral glucose tolerance test (OGTT) under the old Australasian Diabetes in Pregnancy Society guidelines (fasting glucose ≥5.5 mmol/L or 2-h glucose ≥8.0 mmol/L) (1).

Women with GDM twin pregnancies were older, had a higher rate of preexisting hypertension, and were more likely to be from non–Anglo-European backgrounds than …
A Molecular Portrait of De Novo Genes in Yeasts
Authors: Nikolaos Vakirlis, Alex S Hebert, Dana A Opulente, Guillaume Achaz, Chris Todd Hittinger, Gilles Fischer, Joshua J Coon, Ingrid Lafontaine
Journal: Molecular Biology and Evolution (2017)

New genes, with novel protein functions, can evolve "from scratch" out of intergenic sequences. These de novo genes can integrate the cell's genetic network and drive important phenotypic innovations. Therefore, identifying de novo genes and understanding how the transition from noncoding to coding occurs are key problems in evolutionary biology. However, identifying de novo genes is a difficult task, hampered by the presence of remote homologs, fast evolving sequences and erroneously annotated protein coding genes. To overcome these limitations, we developed a procedure that handles the usual pitfalls in de novo gene identification and predicted the emergence of 703 de novo gene candidates in 15 yeast species from 2 genera whose phylogeny spans at least 100 million years of evolution. We validated 85 candidates by proteomic data, providing new translation evidence for 25 of them through mass spectrometry experiments. We also unambiguously identified the mutations that enabled the transition from noncoding to coding for 30 Saccharomyces de novo genes. We established that de novo gene origination is a widespread phenomenon in yeasts, only a few being ultimately maintained by selection. We also found that de novo genes preferentially emerge next to divergent promoters in GC-rich intergenic regions where the probability of finding a fortuitous and transcribed ORF is the highest. Finally, we found a more than 3-fold enrichment of de novo genes at recombination hot spots, which are GC-rich and nucleosome-free regions, suggesting that meiotic recombination contributes to de novo gene emergence in yeasts.
Clonal B-Cell Lymphocytosis with Marginal Zone Features and Splenic Marginal Zone Lymphoma Share a Similar Cytogenetic and Mutational Profile
Authors: Paul Legendre, Olivier Kosmider, Coralie Derrieux, Nicolas Chapuis, Isabelle Radford-Weiss, Hélène Guermouche, Barbara Burroni, Julie Bruneau, Bénédicte Deau, Richard Delarue, Olivier Hermine, Didier Bouscary, David Sibon
Journal: Blood (2016)
Stressing Out PanIN: NRF2 Pushes over the Edge
Authors: Laura Torrente, Gina M. DeNicola
Journal: Cancer Cell (2017)

The mechanisms by which chronic stress promote the development of pancreatic ductal adenocarcinoma (PDAC) are poorly defined. In this issue of Cancer Cell, Todoric et al. discover a role for impaired autophagy in the development of PDAC through p62-mediated activation of NRF2.
Essential thrombocythemia vs. pre-fibrotic/early primary myelofibrosis: discrimination by laboratory and clinical data
Authors: Martin Schalling, Andreas Gleiss, Bettina Gisslinger, Albert Wölfler, Veronika Buxhofer-Ausch, Georg Jeryczynski, Maria-Theresa Krauth, Ingrid Simonitsch-Klupp, Christine Beham-Schmid, Jürgen Thiele, Heinz Gisslinger
Journal: Blood Cancer Journal (2017)
Synthesis of biguanides and an investigation of their therapeutic effects on brain tumours
Authors: Rita N Buttrus, Kani Haki, Megan F Eynon, Ashleigh J S Smith, Natalia A Blazejczak, Geoffrey J Pilkington, Peter B Nunn, Samantha C Higgins, James R Smith
Journal: Neuro-Oncology (2018)

Metformin (N,N-dimethylbiguanide) is the most widely used anti-diabetic drug to treat type II diabetes. It exhibits blood glucose lowering action by regulating glucose formation in the liver (gluconeogenesis), increases glucose utilisation in muscles and reduces glucose absorption in the intestine. Clinical studies have shown that metformin, and other biguanides (buformin and phenformin), have lowered the risk of different kinds of cancer, such as breast, lung, colon, pancreas, and liver cancers. The purpose of this project is to investigate the efficacy of metformin and other biguanides to treat glioblastoma multiforme (GBM). The first step was to produce these compounds in sufficient quantities and purity, to enable all the necessary in vitro experiments to be carried out. The work presented in this study, reports the synthesis and purification of metformin. Literature methods have been vague and/or purification methods have not been disclosed, partly for commercial reasons. Metformin hydrochloride has been prepared by refluxing a reaction mixture of dimethylamine hydrochloride and dicyandiamide using different molar ratios, different reaction solvents (water, water/methanol, ethanol, toluene, xylene, and butanol), various reaction times (2 to 48 h) and using different recrystallisation solvents. In some cases, solvent extraction was used for further purification. Solid products were analysed using a range of techniques, such as melting points, Fourier Transform Infra-red (FTIR) spectroscopy, 1H and 13C nuclear magnetic resonance (NMR) spectroscopy and high performance liquid chromatography (HPLC). Impurities associated with starting materials and other known side-products, e.g., melamine, were identified. The conditions for the synthesis of pure metformin in good yield were also identified. The project is now moving on to testing the synthesised metformin on various GBM cell lines. Other biguanides, including buformin and phenformin, will also be synthesised, purified and their anti-neoplastic properties towards GBM investigated.
Psychosocial and socioeconomic determinants of cardiovascular mortality in Eastern Europe: A multicentre prospective cohort study
Authors: Taavi Tillmann, Hynek Pikhart, Anne Peasey, Ruzena Kubinova, Andrzej Pajak, Abdonas Tamosiunas, Sofia Malyutina, Andrew Steptoe, Mika Kivimäki, Michael Marmot, Martin Bobak
Journal: PLoS Medicine (2017)

Background Eastern European countries have some of the highest rates of cardiovascular disease (CVD) mortality, much of which cannot be adequately accounted for by conventional CVD risk factors. Psychosocial and socioeconomic factors may affect risk of CVD, but relatively few studies on this issue have been undertaken in Eastern Europe. We investigated whether various psychosocial factors are associated with CVD mortality independently from each other and whether they can help explain differences in CVD mortality between Eastern European populations. Methods Participants were from the Health, Alcohol and Psychological factors in Eastern Europe (HAPIEE) cohort study in Russia, Poland and the Czech Republic, including a total of 20,867 men and women aged 43–74 years and free of CVD at baseline examination during 2002–2005. Participants were followed-up for CVD mortality after linkage to national mortality registries for a median of 7.2 years. Results During the follow-up, 556 participants died from CVD. After mutual adjustment, six psychosocial and socioeconomic factors were associated with increased risk of CVD death: unemployment, low material amenities, depression, being single, infrequent contacts with friends or relatives. The hazard ratios [HRs] for these six factors ranged between 1.26 [95% confidence interval 1.14–1.40] and 1.81 [95% confidence interval 1.24–2.64], fully adjusted for each other, and conventional cardiovascular risk factors. Population-attributable fractions ranged from 8% [4%–13%] to 22% [11%–31%] for each factor, when measured on average across the three cohorts. However, the prevalence of psychosocial and socioeconomic risk factors and their HRs were similar between the three countries. Altogether, these factors could not explain why participants from Russia had higher CVD mortality when compared to participants from Poland/Czech Republic. Limitations of this study include measurement error that could lead to residual confounding; and the possibilities for reverse causation and/or unmeasured confounding from observational studies to lead to associations that are not causal in nature. Conclusions Six psychosocial and socioeconomic factors were associated with cardiovascular mortality, independent of each other. Differences in mortality between cohorts from Russia versus Poland or Check Republic remained unexplained.
Abstract B18: MAGEC1 and BAGE2 mRNA expression can be used to monitor chemotherapy treatment responses in multiple myeloma patients and pre-empt clinical relapse
Authors: Karen Shires, Kirsty Wienand
Journal: Cancer Research (2017)

Abstract Being able to monitor the levels of malignant progenitor cells in Multiple Myeloma, as opposed to the plasma cell burden or clinical symptoms alone, will be an important move forward in the management of this disease. The expression of cancer testis antigen MAGE C1 has been previously linked to the malignant stem cell at all stages of this disease, while BAGE2 expression has been clearly associated with the progression to a more advanced disease stage and thus clonal evolution. We investigated the use of a multiplex QRTPCR approach to monitor the co-expression of these transcripts in the peripheral blood as an alternative monitoring methodology. We compared the levels of MAGEC1 and BAGE2 mRNA in the PBMC population to serum M protein and serum beta 2 microglobulin levels at 3-monthly intervals over a 2-year period for 12 patients on chemotherapy regimens. The analysis indicated that the novel QRTPCR analysis of MAGE C1 expression in the less invasive peripheral blood sample type was extremely relevant as a potential minimal residual disease-monitoring tool. Expression of this cancer testis antigen was detectable in all patients throughout treatment, with comparable increases and decreases to serum M protein and/or serum beta 2 microglobulin, but with the advantage of being able to detect disease at a lower level and potentially signal relapse prior to a full clinical relapse. Expression of BAGE2 was only observed in a few patients, but its expression was clearly associated with a worsening clinical profile. As with MAGEC1, the detection of this transcript occurred at least 3 months prior to clinical changes in some patients, indicating its potential use in early medical intervention. Citation Format: Karen Shires, Kirsty Wienand. MAGEC1 and BAGE2 mRNA expression can be used to monitor chemotherapy treatment responses in multiple myeloma patients and pre-empt clinical relapse [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B18.
Nifedipine cream versus sildenafil cream for patients with secondary Raynaud phenomenon: A randomized, double-blind, controlled pilot study
Authors: Ximena Wortsman, Pablo Del Barrio-Díaz, Rodrigo Meza-Romero, Christine Poehls-Risco, Cristián Vera-Kellet
Journal: Journal of the American Academy of Dermatology (2017)