tbuckley/cabot-search huggingface dataset:
Controlled Cardiac Output Studies in Dogs (Part I)
Authors: ERIC C. Elliot
Journal: Circulation Research (1961)

A method lias been presented whereby a semiquantitative estiTiiation of the coronary flow in dogs can be made (within certain experimental limits) by means of a regression equation based on the relationship that coronary flow appears to bear to the product of mean arterial blood pressure times heart rate. The data, from which the regression equation was derived, were obtained by means of the utilization of the "complete right-heart bypass preparation" in seven dogs. The equation for the prediction of coronary return was tested in an additional six dogs, using the "complete right-heart bypass preparation" and the results showed that, if the value for the estimated coronary return were added to the value for caval return, the resultant sum would give a significantly better estimate of the cardiac output than if the value for caval flow only were used as the index.
HGG-23. GLUTAMINOLYSIS INVOLVEMENT AND ITS TARGETING IN PEDIATRIC HIGH GRADE GLIOMAS: A NEW WAY OF TREATMENT
Authors: Quentin Fuchs, Mélanie Frauli, Elisa Ruhland, Celine Keime, Stanislas Mayer, Izzie Jacques Namer, Stephane Schann, Monique Dontenwill, Natacha Entz-Werlé
Journal: Neuro-Oncology (2019)

Gliomas are the most common type of pediatric brain tumors. One third of them are high grade gliomas (pHGG) with a significant dismal prognosis and a very poor therapeutic arsenal. So, new therapeutic ideas are needed to counterpart the high resistance to current treatments. Therefore, our team focused recently on the glutaminolysis switch, which was previously described in our work targeting mTor and HIF1 in pHGG cell lines. Therefore, to go further and understand its role in pHGG, we started with metabolomics analyses in our monocentric cohort of 34 pediatric high grade gliomas (14 DIPG, 10 thalamic and 10 sus-tentoriel high grade gliomas). First, we were testing 14 appropriate fresh-frozen samples at diagnosis for metabolomics and used the 34 FFPE specimens for validations. A second step of in vitro experimentation was performed to target specifically the different metabotropic glutamate receptors (mGluR) involved in pHGG glutamine metabolism. We used 6 HGG cell lines mutated or not for H3.3 K27M variant. In terms of results, metabolomics, done by HRMAS NMR, confirmed in tumors and in cell lines a high level of glutaminolysis, which is currently confirmed in all tumors by immunohistochemistry. This specific metabolic switch was also significantly observed by RNAsequencing analyses in our primary derived cell lines cultured in hypoxic conditions. Multiple genes, like mGluR8, mGluR2/3 and several subunits of the glutamate ionotropic receptors, were highly expressed. The in vitro blockade with mGluR2/3 NAM showed, finally, in our cell lines a significant decrease of proliferation, when using them as a single drug therapy, but also in association with temozolomide. This first in vitro work will be confirmed in our PDX mouse models of pHGG. Nevertheless, taking together, these promising results seem to be a scientifically-based rationale for testing mGluR antagonists as adjuvant therapy in pHGGs.
The Two Cultures of Computational Psychiatry
Authors: Daniel Bennett, Steven M. Silverstein, Yael Niv
Journal: JAMA Psychiatry (2019)

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In young, healthy men, the relationship between serum osteocalcin levels and metabolic profile is mediated through fat mass
Authors: Charlotte Verroken, Jean Kaufman, Stefan Goemaere, Kaatje Toye, Bruno Lapauw
Journal: Endocrine Reviews (2015)

BACKGROUND: The osteoblast-derived protein osteocalcin has been proposed as a mediator in the cross-talk between bone and energy metabolism. However, results from human studies investigating the associations between osteocalcin and metabolic parameters are inconsistent. Moreover, few studies have investigated these relationships in young and healthy individuals. 
OBJECTIVE: We aimed to investigate the associations between osteocalcin levels and parameters reflecting metabolic health in a cohort of young, healthy men. 
METHODS: A cross-sectional, population-based sibling pair study was conducted, including 1001 healthy men aged 25-45 years. Clinical assessments included height, weight, waist/hip ratio (WHR), DXA-derived body composition and blood pressure. Total cholesterol, glucose, insulin, leptin, adiponectin, SHBG and total osteocalcin levels were determined in fasting serum samples. Insulin resistance was evaluated using the homeostasis model assessment of insulin resistance (HOMA-IR). Testosterone levels were determined using LCMS-MS, free and bioavailable testosterone levels were calculated. Cross-sectional relationships were assessed using linear mixed-effects modeling.
RESULTS: Osteocalcin levels were available in 996 men (mean 22.7+/-6.5 ng/mL, normal range 14-42 ng/mL) and were inversely associated with age (β=-0.37; p<0.001), BMI, fat mass, waist circumference, WHR, truncal and appendicular fat mass and total lean mass (β=-0.07--0.29; p<0.001 for all associations except for total lean mass: p=0.019), whereas they were positively associated with percentage lean mass (β=0.28; p<0.001). In addition, osteocalcin levels were inversely related to fasting glucose and insulin levels and to HOMA-IR index, as well as to total cholesterol levels, leptin, diastolic blood pressure and mean arterial pressure (β=-0.10--0.26; p<0.001 for all associations except for mean arterial pressure: p=0.001). Moreover, a positive correlation existed with adiponectin levels (β=0.08; p=0.033) and with total, bioavailable and free testosterone levels (β=0.07-0.14; p<0.001, p=0.001 and p=0.024, respectively). After adjustment for age and fat mass, most of these associations attenuated and were no longer significant, except for the inverse associations between osteocalcin and fasting glucose (β=-0.07; p=0.034) and leptin levels (β=-0.04; p=0.031). Fat mass, on the other hand, was independently associated with a less favorable metabolic profile and lower testosterone levels. 
CONCLUSION: In this cohort of young, healthy men, the relation between lower serum osteocalcin levels and a less favourable metabolic profile was mediated through fat mass. This may reflect an inverse association between fat mass and bone turnover or, more hypothetically, the reciprocal differentiation of mesenchymal stem cells towards the osteogenic versus adipogenic lineage.
Framework for patient-ventilator asynchrony during long-term non-invasive ventilation
Authors: Jesus Gonzalez-Bermejo, Jean-Paul Janssens, Claudio Rabec, Christophe Perrin, Frédéric Lofaso, Bruno Langevin, Annalisa Carlucci, Manel Lujan
Journal: Thorax (2019)

Episodes of patient-ventilator asynchrony (PVA) occur during acute and chronic non-invasive positive pressure ventilation (NIV). In long-term NIV, description and quantification of PVA is not standardised, thus limiting assessment of its clinical impact. The present report provides a framework for a systematic analysis of polygraphic recordings of patients under NIV for the detection and classification of PVA validated by bench testing. The algorithm described uses two different time windows: rate asynchrony and intracycle asynchrony. This approach should facilitate further studies on prevalence and clinical impact of PVA in long-term NIV.
MEDU-08. MiR-1253 POSSESSES NOVEL TUMOR SUPPRESSOR PROPERTIES IN PEDIATRIC MEDULLOBLASTOMA
Authors: Ranjana Kanchan, Naveen Kumar Perumal, Pranita Atri, Ishwor Thapa, Mohd W Nasser, Deborah Perry, Surinder K Batra, Sidhartha Mahapatra
Journal: Neuro-Oncology (2019)

Medulloblastoma (MB), the most common malignant pediatric brain tumor, is divided into four primary subgroups, i.e. SHH, WNT, and non-SHH/WNT groups 3 and 4. The most frequent cytogenetic abnormality in MB, i.e. i17q, distinguishes the non-SHH/WNT subgroups. Haploinsufficiency of 17p13.3 is reported in up to 50% of non-SHH/WNT MB cases and has been correlated with poor prognosis. At the terminal end of this locus is miR-1253, which is exclusively expressed in the brain and an important regulator of bone morphogenic proteins that play a critical role in cerebellar development. Recently, miR-1253 was identified as a tumor suppressor gene in non-small cell lung cancer (NSCLC) and osteosarcoma. Two oncogenic targets of miR-1253, i.e. TGIF2 and ALX4, have recently been identified in SHH medulloblastoma. Based upon these observations, we hypothesized that miR-1253 may be a tumor suppressor gene in pediatric medulloblastoma. Starting with an expression analysis of miR-1253, we found deregulation in 28 pediatric clinical samples (5 SHH, 10 Grp 3, 13 Grp 4) and 7 medulloblastoma cell lines. Moreover, the locus is hypermethylated in Grp 3 and Grp 4 MB. Expectedly, de-methylation using 5-AzaC resulted in rapid recovery of expression with a concurrent decline in cell proliferation, a property abrogated using an miR-1253 inhibitor. Overexpression of miR-1253 in tumor cell lines led to a reduction in cell proliferation, colony formation, migration and invasiveness, concomitant with activation of apoptotic pathways and reduced stemness. In subcutaneously transplanted HDMB03 cells overexpressing miR-1253, tumor size was noted to be significantly lower. Using high throughput RNA sequencing analysis and luciferase reporter assay, we further identified 2 putative oncogenic targets of miR-1253, i.e. CDK6 and CD276. Taken together, these data purport that in pediatric medulloblastoma, miR-1253 is epigenetically silenced by hypermethylation and possesses tumor suppressor qualities by downregulating its oncogenic targets CDK6 and CD276.
Abstract 18614: Rheumatic Heart Disease Screening in Schools Through Portable Echocardiography: Data From the PROVAR Study
Authors: Bruno R Nascimento, Andrea Z Beaton, Maria do Carmo P Nunes, Catherine L Webb, Adriana C Diamantino, Kaciane K Bruno, Cassio O Miri, Gabriel T Pereira, Eduardo L Lopes, Camila G Ferreira, Luciana C Lafeta, Antonio Luiz P Ribeiro, Craig Sable
Journal: Circulation (2015)

Introduction: The accuracy of clinical examination is limited for early diagnosis of Rheumatic Heart Disease (RHD). The 2012 World Heart Federation (WHF) Criteria provides standardized echocardiographic (echo) guidelines for diagnosis of RHD. There is sparse data on echo prevalence of RHD in Brazil. Objective: Assess the prevalence of RHD in students (6-18 years) from public schools in low-income areas in Belo Horizonte, Brazil. Methods: Over 4-days, experts used standard portable echo machines (GE, Vivid-Q) and the 2012 WHF Criteria to determine RHD prevalence. All consented and present children at the visited schools were eligible for participation. Studies identified as abnormal were blindly read by a second cardiologist, with non-agreement adjudicated by a third. RHD prevalence by gender and age (5-11 &amp; 12-18) were compared using Fisher’s Exact Test. Results: A total of 1381 students were screened across four schools in urban Belo Horizonte, Brazil. The mean age was 13.6±2.8 years, range 5-18 years; 59.3% were female. The prevalence of RHD was 3.8% (53/1381): 3.4% borderline RHD (n=47) and 0.4% definite RHD (n=6). Of these cases, 46 (86.8%) had pathologic mitral regurgitation (≥2cm, seen in 2-views, pan-systolic, and velocity ≥3m/sec) and 7 had pathologic aortic regurgitation (≥1cm, seen in 2-views, pan-diastolic, and velocity ≥3m/sec). One child had mixed mitral and aortic valve disease. There were no cases of mitral or aortic stenosis. There was no difference in RHD prevalence between males and females (p=0.57), but older children had a higher prevalence rate (5-11 years 1.3% vs. 12-18 years 4.5%, p=0.01). Minor congenital heart disease was detected in 8 additional children (5.8%), including one large ASD that was referred for closure. Conclusions: WHF Criteria make it possible to obtain and accurately compare echo prevalence of RHD among different regions of the world. The PROVAR study shows that, among children living in low-socioeconomic conditions in urban Brazil, RHD remains a significant health burden, comparable to that in other low-resource communities. Screening older children has higher yield. Contemporary data such as these provide justification for investing in comprehensive RHD control programs both in Brazil, and around the globe.
Abstract 17658: Prevalence and Predictors of Left Ventricular Reverse Remodeling After Radiofrequency Catheter Ablation for Atrial Fibrillation in Patients With Heart Failure and Reduced Ejection Fraction
Authors: Masato Okada, Koichi Inoue, Yuko Hirao, Koji Tanaka, Takafumi Oka, Yuichi Ninomiya, Nobuaki Tanaka, Ryo Nakamaru, Hiroyuki Inoue, Yasushi Koyama, Katsuomi Iwakura, Kenshi Fujii
Journal: Circulation (2017)

Introduction: Atrial fibrillation (AF) causes electrical and structural remodeling of both the left atrium (LA) and the left ventricle (LV). Restoration of sinus rhythm can improve cardiac function...
Detection of extranodal and spleen involvement by FDG‐PET imaging predicts adverse survival in untreated follicular lymphoma
Authors: Frédérique St‐Pierre, Stephen M. Broski, Betsy R. LaPlant, Kay Ristow, Matthew J. Maurer, William R. Macon, Thomas M. Habermann, Stephen M. Ansell, Carrie A. Thompson, Ivana N. M. Micallef, Grzegorz S. Nowakowski, Thomas E. Witzig
Journal: American Journal of Hematology (2019)

Abstract Predicting early clinical failure in patients with untreated follicular lymphoma (FL) is important but difficult. This study aimed to determine the incidence and patterns of extranodal (EN) and spleen disease using PET/CT, and assess their utility in predicting early clinical failure. PET/CT images from 613 cases of untreated FL (2003‐2016) were reviewed. The location and number of EN sites, patterns of bone involvement, and splenic involvement were recorded. Outcomes were assessed using event‐free survival (EFS), overall survival (OS), and early clinical failure at 24 months (EFS24). So, 49% (301/613) of patients had PET/CT‐detected EN involvement, and 28% (171/613) had spleen involvement. The presence of ≥2 EN sites, spleen, bone or soft tissue involvement all predicted failure to achieve EFS24. Presence of ≥2 EN sites and bone involvement pattern were also predictive of OS in a univariate analysis. In a multivariate analysis with FLIPI‐2 factors, spleen involvement, pattern of bone involvement, and soft tissue involvement independently predicted a lower EFS (HR 1.49 (1.11‐2.00), P = .007; HR 1.71 (1.10‐2.65), P = .017; and HR 1.67 (1.06‐2.62), P = .026, respectively). When the multivariate analysis was performed using PRIMA‐PI factors (marrow and B2M), the number of EN sites was an independent prognostic factor for inferior OS (HR 2.28; P = .05). Baseline PET/CT identifies EN involvement in nearly half of patients with untreated FL. The presence of ≥2 EN sites, bone, soft tissue, or splenic involvement predicts early clinical failure. These results, when combined with other factors, may better identify high‐risk patients and guide therapy.
Oral Gene Delivery: NPC1L1‐Targeted Cholesterol‐Grafted Poly(β‐Amino Ester)/pDNA Complexes for Oral Gene Delivery (Adv. Healthcare Mater. 8/2019)
Authors: Yuan Liu, Dan Chen, Jialin Li, Dengning Xia, Miaorong Yu, Jinsong Tao, Xinxin Zhang, Li Li, Yong Gan
Journal: Advanced Healthcare Materials (2019)

In article number 1800934, Yong Gan and co-workers synthesize a cholesterol-grafted poly (β-amino ester) (CH-PHP), which can electrostatically interact with plasmid DNA to form a CH-PHP/DNA complex (CPNC) with mitigated cytotoxicity, enhanced enzyme resistance, and improved gene condensing ability. This complex can target the Niemann-Pick C1-like (NPC1L1) receptor, localized on the apical membrane of intestinal epithelia cells, to improve oral gene delivery efficacy.
Abstract 20780: Cardiac Progenitor Cell's Secretome in Health and Heart Failure: Insight to Autocrine Rescue Mission
Authors: Rasmita Samal, Elke Hammer, Stephanie Koenemann, Praveen K Sappa, Manuela G Salazar, Kristin Wenzel, Uwe Völker, Stephan Felix
Journal: Circulation (2017)

Introduction: The cellular microenvironment of cardiac progenitor cells plays a crucial role in the maintenance of heart function and the regeneration of damaged myocardium. Hypothesis: We aimed to...
SIG-03. HHIP-AS1 PROMOTES TUMOR SURVIVAL THROUGH STABILIZING DYNEIN COMPLEX 1 IN HEDGEHOG DRIVEN HUMAN BRAIN TUMORS
Authors: Jasmin Bartl, Antoine Forget, Marco Zanini, Daniel Picard, Nan Qin, Arndt Borkhardt, Guido Reifenberger, Olivier Ayrault, Marc Remke
Journal: Neuro-Oncology (2019)

Aberrant activation of the sonic hedgehog (SHH) pathway is one of the key drivers of tumorigenesis in aggressive pediatric brain tumors. However, SHH pathway inhibitors for the treatment of brain tumors demonstrated only limited responses in clinical trials indicating that a better understanding of the human SHH pathway is needed. Using an integrative transcriptomic analysis of several thousand normal and neoplastic tissues with and without SHH activation, we identified HHIP-AS1 as an important long non-coding RNA that is strongly associated with SHH signaling in pediatric brain tumors. HHIP-AS1 expression was significantly up- and downregulated upon SHH activation or inhibition, respectively. We also revealed that HHIP-AS1 shares a bidirectional promoter with HHIP and that common transcription factors control both expressions. Transient and stable HHIP-AS1 knockdown (KD) led to a significant less aggressive phenotype of medulloblastoma and ATRT in vitro and in vivo (in cell lines, patient-derived primary cultures and in orthotopic mouse models). In detail, we observed a significant reduction of proliferation, cell viability, clonogenicity, and an induction of cell cycle arrest with a mitotic arrest upon HHIP-AS1 KD. Additionally, RNA sequencing and proteomic analysis unraveled cytoplasmic dynein complex 1 intermediate chain 2 (DYNC1I2), which is a key mitosis regulator, as a target of HHIP-AS1. Further investigations revealed that HHIP-AS1 stabilizes DYNC1I2 via RNA–RNA interaction and that DYNC1I2 overexpression rescued the observed phenotypes. Taken together, our analysis demonstrates that HHIP-AS1 promotes tumorigenesis in SHH-driven brain tumors and identify a novel lncRNA as a component in the human SHH signaling pathway. STEM CELLS
Induction of Inflammation and Fibrosis by Semaphorin 4A in Systemic Sclerosis
Authors: Tiago Carvalheiro, Alsya J. Affandi, Beatriz Malvar‐Fernández, Ilse Dullemond, Marta Cossu, Andrea Ottria, Jorre S. Mertens, Barbara Giovannone, Femke Bonte‐Mineur, Marc R. Kok, Wioleta Marut, Kris A. Reedquist, Timothy R. Radstake, Samuel García
Journal: Arthritis & Rheumatology (2019)

Objective To analyze the potential role of semaphorin 4A (Sema4A) in inflammatory and fibrotic processes involved in the pathology of systemic sclerosis ( SS c). Methods Sema4A levels in the plasma of healthy controls (n = 11) and SS c patients (n = 20) were determined by enzyme‐linked immunosorbent assay ( ELISA ). The expression of Sema4A and its receptors in monocytes and CD 4+ T cells from healthy controls and SS c patients (n = 6–7 per group) was determined by ELISA and flow cytometry. Th17 cytokine production by CD 4+ T cells (n = 5–7) was analyzed by ELISA and flow cytometry. The production of inflammatory mediators and extracellular matrix ( ECM ) components by dermal fibroblast cells (n = 6) was analyzed by quantitative polymerase chain reaction, ELISA , Western blotting, confocal microscopy, and ECM deposition assay. Results Plasma levels of Sema4A, and Sema4A expression by circulating monocytes and CD 4+ T cells, were significantly higher in SS c patients than in healthy controls ( P &lt; 0.05). Inflammatory mediators significantly up‐regulated the secretion of Sema4A by monocytes and CD 4+ T cells from SS c patients ( P &lt; 0.05 versus unstimulated SS c cells). Functional assays showed that Sema4A significantly enhanced the expression of Th17 cytokines induced by CD 3/ CD 28 in total CD 4+ T cells as well in different CD 4+ T cell subsets ( P &lt; 0.05 versus unstimulated SS c cells). Finally, Sema4A induced a profibrotic phenotype in dermal fibroblasts from both healthy controls and SS c patients, which was abrogated by blocking or silencing the expression of Sema4A receptors. Conclusion Our findings indicate that Sema4A plays direct and dual roles in promoting inflammation and fibrosis, 2 main features of SS c, suggesting that Sema4A might be a novel therapeutic target in SS c.
Influence of the Urban Exposome on Birth Weight
Authors: Mark J. Nieuwenhuijsen, Lydiane Agier, Xavier Basagaña, Jose Urquiza, Ibon Tamayo-Uria, Lise Giorgis-Allemand, Oliver Robinson, Valérie Siroux, Léa Maitre, Montserrat de Castro, Antonia Valentin, David Donaire, Payam Dadvand, Gunn Marit Aasvang, Norun Hjertager Krog, Per E. Schwarze, Leda Chatzi, Regina Grazuleviciene, Sandra Andrusaityte, Audrius Dedele, Rosie McEachan, John Wright, Jane West, Jesús Ibarluzea, Ferran Ballester, Martine Vrijheid, Rémy Slama
Journal: Environmental Health Perspectives (2019)

The exposome is defined as the totality of environmental exposures from conception onwards. It calls for providing a holistic view of environmental exposures and their effects on human health by evaluating multiple environmental exposures simultaneously during critical periods of life.We evaluated the association of the urban exposome with birth weight.We estimated exposure to the urban exposome, including the built environment, air pollution, road traffic noise, meteorology, natural space, and road traffic (corresponding to 24 environmental indicators and 60 exposures) for nearly 32,000 pregnant women from six European birth cohorts. To evaluate associations with either continuous birth weight or term low birth weight (TLBW) risk, we primarily relied on the Deletion-Substitution-Addition (DSA) algorithm, which is an extension of the stepwise variable selection method. Second, we used an exposure-by-exposure exposome-wide association studies (ExWAS) method accounting for multiple hypotheses testing to report associations not adjusted for coexposures.The most consistent statistically significant associations were observed between increasing green space exposure estimated as Normalized Difference Vegetation Index (NDVI) and increased birth weight and decreased TLBW risk. Furthermore, we observed statistically significant associations among presence of public bus line, land use Shannon's Evenness Index, and traffic density and birth weight in our DSA analysis.This investigation is the first large urban exposome study of birth weight that tests many environmental urban exposures. It confirmed previously reported associations for NDVI and generated new hypotheses for a number of built-environment exposures. https://doi.org/10.1289/EHP3971.